Role of leptin in the pancreatic β-cell: effects and signaling pathways

in Journal of Molecular Endocrinology

Leptin plays an important role in the control of food intake, energy expenditure, metabolism, and body weight. This hormone also has a key function in the regulation of glucose homeostasis. Although leptin acts through central and peripheral mechanisms to modulate glucose metabolism, the pancreatic β-cell of the endocrine pancreas is a critical target of leptin actions. Leptin receptors are present in the β-cell, and their activation directly inhibits insulin secretion from these endocrine cells. The effects of leptin on insulin occur also in the long term, since this hormone inhibits insulin gene expression as well. Additionally, β-cell mass can be affected by leptin through changes in proliferation, apoptosis, or cell size. All these different functions in the β-cell are triggered by leptin as a result of the large diversity of signaling pathways that this hormone is able to activate in the endocrine pancreas. Therefore, leptin can participate in glucose homeostasis owing to different levels of modulation of the pancreatic β-cell population. Furthermore, it has been proposed that alterations in this level of regulation could contribute to the impairment of β-cell function in obesity states. In the present review, we will discuss all these issues with special emphasis on the effects and pathways of leptin signaling in the pancreatic β-cell.

Abstract

Leptin plays an important role in the control of food intake, energy expenditure, metabolism, and body weight. This hormone also has a key function in the regulation of glucose homeostasis. Although leptin acts through central and peripheral mechanisms to modulate glucose metabolism, the pancreatic β-cell of the endocrine pancreas is a critical target of leptin actions. Leptin receptors are present in the β-cell, and their activation directly inhibits insulin secretion from these endocrine cells. The effects of leptin on insulin occur also in the long term, since this hormone inhibits insulin gene expression as well. Additionally, β-cell mass can be affected by leptin through changes in proliferation, apoptosis, or cell size. All these different functions in the β-cell are triggered by leptin as a result of the large diversity of signaling pathways that this hormone is able to activate in the endocrine pancreas. Therefore, leptin can participate in glucose homeostasis owing to different levels of modulation of the pancreatic β-cell population. Furthermore, it has been proposed that alterations in this level of regulation could contribute to the impairment of β-cell function in obesity states. In the present review, we will discuss all these issues with special emphasis on the effects and pathways of leptin signaling in the pancreatic β-cell.

Keywords:

Introduction

A fine regulation of pancreatic β-cell function is essential for the control of plasma glucose homeostasis and nutrient metabolism. β-cell secretion and mass are dynamic features that adapt in the short and/or long term to the insulin requirements of the organism (Sachdeva & Stoffers 2009). These insulin needs depend on multiple factors, including nutritional status and metabolic, hormonal, and neural signals. This functional plasticity also occurs during physiological or pathological situations such as pregnancy or obesity respectively (Sachdeva & Stoffers 2009). The regulation of β-cell function in the short and long term allows for an adequate level of plasma insulin levels, which restores plasma glucose concentrations to normoglycemia by inducing glucose uptake and accumulation as glycogen and fatty acids, principally in muscle, liver, and adipose tissue. However, a decrease in β-cell mass or impaired β-cell function can lead to abnormal plasma insulin levels that can promote glucose intolerance and diabetes.

Among the different risk factors for the development of diabetes, obesity is a major one. The progression of obese individuals to diabetes is attributed to an altered compensation in β-cell mass and function in response to insulin demand (Sachdeva & Stoffers 2009). Obesity involves an increasing accumulation of adipose tissue and enhanced release of adipokines. Among others, leptin has been revealed as an important regulator of pancreatic β-cell function at different levels including insulin gene expression, insulin secretion, apoptosis, and cell growth. Thus, in addition to its central actions for the control of glucose metabolism (Morton & Schwartz 2011), leptin can modulate glucose homeostasis owing to these different direct effects on the β-cell. Additionally, it has been proposed that alterations in leptin signaling in the β-cell might be involved in diabetes in obese individuals (Seufert 2004). In the next sections we will focus on the different leptin actions in the pancreatic β-cell and how this hormone regulates the function of these endocrine cells.

Leptin and glucose homeostasis

Leptin plays an important function in the control of food intake, energy expenditure, metabolism, and body weight (Fruhbeck 2006). It has been also demonstrated that this hormone has a key role in the regulation of glucose homeostasis acting through both central and peripheral mechanisms. Actually, animal models with defects in leptin or in leptin receptors such as ob/ob and db/db mice respectively develop insulin resistance, hyperinsulinemia, and impaired glucose homeostasis (Genuth et al. 1971, Dubuc 1976). Leptin administration to ob/ob mice reduces plasma glucose levels, an effect that is in part independent of any reduction in body weight (Pelleymounter et al. 1995, Schwartz et al. 1996). Additionally, leptin treatment reduces the hyperinsulinemia of these animals (Pelleymounter et al. 1995, Seufert et al. 1999b). Exogenous leptin treatment also improves plasma insulin and glucose concentrations in animal models of lipodystrophy, which lack adipose tissue and normal leptin levels (Shimomura et al. 1999). Moreover, central or peripheral leptin administration restores normoglycemia in animal models of type 1 (Chinookoswong et al. 1999, Fujikawa et al. 2010, Wang et al. 2010, Denroche et al. 2011) and type 2 diabetes (Park et al. 2010, Cummings et al. 2011). Similar observations have been reported in type 1 diabetic animals after adenoviral transfer of the leptin gene (Yu et al. 2008, Kojima et al. 2009). Likewise, cross-mating of leptin-expressing transgenic mice with Akita mice, a model of insulin-dependent diabetes, led to animals with better glucose tolerance and insulin sensitivity (Naito et al. 2011).

Although it has been reported that leptin affects glucose homeostasis mainly through actions on the hypothalamus (Coppari et al. 2005, Huo et al. 2009, Fujikawa et al. 2010, Hill et al. 2010, German et al. 2011), leptin peripheral actions are also involved. Leptin can directly affect glucose metabolism or interact with insulin actions in the skeletal muscle, liver, and adipose tissue (Berti et al. 1997, Ceddia et al. 1999a,b, Perez et al. 2004). Furthermore, besides these peripheral tissues, the pancreatic β-cell is a key target of leptin. Numerous in vivo and in vitro studies have shown that this hormone activates a diversity of events in the β-cell, which will be reviewed in the next sections. Additionally, experiments in knockout (KO) mice with specific deletion of the leptin receptor in the pancreas or in the β-cell and the hypothalamus have shown alterations in glucose homeostasis as well as in β-cell function and mass in these animals (Covey et al. 2006, Morioka et al. 2007). Leptin signaling defects in β-cells lacking the leptin receptor lead to hyperinsulinemia, which develops prior to insulin resistance (Gray et al. 2010). Moreover, administration of leptin antagonists to normal mice increases plasma insulin levels and promotes insulin resistance (Levi et al. 2011). Thus, leptin effects on β-cell function are also an important component of the leptin ability to regulate glucose homeostasis.

Leptin receptors in the pancreatic β-cell

Leptin, a peptidic hormone comprising 167 amino acids, is mainly released by adipocytes, but it is also detected in numerous tissues such as lymphoid tissues, placenta, and ovaries, among others (Mantzoros et al. 2011). Although its plasma concentrations are highly correlated with the adipose tissue mass, several factors, from circadian mechanisms to feeding behavior, can regulate its levels (Licinio et al. 1997). The leptin receptor (OBR (LEPR)) gene produces several splicing variants that lead to six isoforms (from ObRa to ObRf) (Fig. 1). All these variants have a common extracellular domain, but the intracellular site varies for each isoform. ObRb is the long full-length isoform and it is considered the main one involved in the transduction of intracellular signals (Mantzoros et al. 2011). Although some variants like ObRa may have some signaling capacity (Fruhbeck 2006), the function of the short isoforms has been attributed to leptin binding and transport in plasma, leptin transport across the blood–brain barrier, or renal leptin clearance (Meyer et al. 1997, Morton & Schwartz 2011). The long form of the leptin receptor has been reported in β-cell lines derived from mouse (βTC-3 and MIN-6), hamster (HIT), rat (INS-1 and RINm5F) as well as pancreatic islets of rat, mouse and human (Kieffer et al. 1996, 1997, Emilsson et al. 1997, Fehmann et al. 1997b, Tanizawa et al. 1997, Poitout et al. 1998, Seufert et al. 1999b). The expression of OBRB in the β-cell has been further confirmed by studies in KO mice with specific disruption of the Obr(Lepr) gene either in the pancreas or in the β-cell and hypothalamus (Covey et al. 2006, Morioka et al. 2007).

Figure 1
Figure 1

The leptin receptor has six isoforms obtained by alternative splicing, which are designated ObRa, ObRb, ObRc, ObRd, ObRe, and ObRf. While the extracellular domain is common for all of these isoforms, the intracellular domain differs from one variant to another. The number below each form indicates the number of amino acids characteristic of each isoform. The box 1 motif is required for JAK interaction and activation. However, only the long form (ObRb) contains motifs for the complete activation of the JAK/STAT pathway. Three tyrosine residues, whose phosphorylation is important for leptin signaling, are indicated in ObRb: Y985 interacts with the SH2-containing protein tyrosine phosphatase 2, Y1077 with STAT5, and Y1138 with STAT3.

Citation: Journal of Molecular Endocrinology 49, 1; 10.1530/JME-12-0025

The leptin receptor belongs to the class I cytokine receptor family (Fruhbeck 2006). The main signaling pathway initiated by this receptor family involves the activation of JAKs and STATs. In the case of ObRb, binding of leptin to the receptor activates JAK proteins that phosphorylate several tyrosine residues on the leptin receptor, allowing for the recruitment and phosphorylation of STATs. Then, STAT proteins dimerize, translocate to the nucleus, and act as gene transcription regulators (Fruhbeck 2006; Fig. 2). However, there are other pivotal signaling pathways, whose activation mediates the great diversity of leptin effects in the pancreatic β-cell, and that will be described in the following sections. These include PI3-kinase (PI3K), MAP kinase, c-Jun amino-terminal kinases (JNK), and nitric oxide (NO) among others (Lee et al. 2011).

Figure 2
Figure 2

Leptin binding to its receptor activates the associated JAK-2 tyrosine kinase, which subsequently phosphorylates intracellular tyrosine residues of the receptor. This leads to the activation of STAT3, which dimerizes and migrates to the nucleus, where it works as a transcription factor, promoting the expression of genes like neuropeptide Y (NPY). STAT3 also induces the expression of SOCS3, a protein that acts as a negative regulator of the JAK/STAT pathway. Likewise, PTP1B is another protein that negatively regulates the JAK/STAT route.

Citation: Journal of Molecular Endocrinology 49, 1; 10.1530/JME-12-0025

Regulation of insulin secretion by leptin

Although some studies have indicated no effect or even a stimulatory action (Tanizawa et al. 1997, Leclercq-Meyer & Malaisse 1998, Ahren & Havel 1999), it is well accepted that leptin inhibits β-cell insulin secretion. Some of these discrepancies most likely come from the diverse conditions used in the different studies, including in vivo experiments, perfused pancreas, isolated islets, and β-cell lines, as well as from the different concentrations employed. Actually, several studies have reported U-shaped dose–responses for leptin (Zhao et al. 1998, Brown et al. 2002). At doses of 0.5–100 nM, leptin reduces insulin release in HIT-T15, β-TC6, and INS-1 cells (Kulkarni et al. 1997, Zhao et al. 1998, Tsiotra et al. 2001, Kuehnen et al. 2011). Similar observations have been obtained in isolated pancreatic islets of ob/ob and normal mice, rats as well as in perfused pancreas at concentrations ranging from 1 pM to 100 nM (Kieffer et al. 1997, Kulkarni et al. 1997, Pallett et al. 1997, Zhao et al. 1998). These effects have been reported for a variety of glucose concentrations from low to high levels. In contrast, in human islets, while some studies observed this inhibitory effect only at low glucose concentrations (Kulkarni et al. 1997, Seufert et al. 1999b), others reported reduced insulin secretion at high glucose levels (16–22 mM) with chronic leptin incubations (Brown et al. 2002). Thus, much work is necessary to address whether leptin effects on insulin secretion depend on glucose concentrations in human islets. Additionally, while no leptin effect has been reported in isolated human islets at 1–50 ng/ml during short-term incubations, significant changes in glucose-induced insulin secretion were observed under chronic leptin exposure (Lupi et al. 1999). The role of leptin in the regulation of insulin levels has been explored as well as in vivo in mice and rat confirming the suppressing function of this hormone (Kulkarni et al. 1997, Cases et al. 2001).

Several signaling events seem to be involved in this inhibitory role of leptin in insulin secretion. In β-cells, glucose metabolism increases the intracellular ATP/ADP ratio, which blocks ATP-dependent K+ (KATP) channels, inducing a plasma membrane depolarization that activates voltage-dependent C2+ channels (VDCC). This activation leads to cytosolic Ca2+ influx and exocytosis. It has been reported that leptin activates KATP channels in β-cells from ob/ob mice, leading to diminished Ca2+ influx (Kieffer et al. 1997). Similarly, leptin reduces glucose-induced Ca2+ signals in human islets (Seufert et al. 1999b) and INS-1 cells (Kuehnen et al. 2011). In the rat cell line CRI-G1, KATP channel opening by leptin was associated with PI3K-induced reorganization of the actin cytoskeleton (Harvey et al. 2000), a process that was also confirmed in mouse pancreatic β-cells (Ning et al. 2006). Alternatively, it has been shown that leptin can reduce glucose transport and ATP levels in INS-1 cells, thereby affecting KATP channel activity (Lam et al. 2004). Conversely, leptin decreases glucose-induced expression of uncoupling protein-2 (UCP-2) in human islets (Brown et al. 2002), which should favor the coupling of ATP production from respiration, allowing for higher ATP/ADP levels. Recently, it has been shown in INS-1 cells that reduced Ca2+ influx by leptin could also be related to a decreased activity of the protein phosphatase 1 enzyme (Kuehnen et al. 2011). In addition to the effect on KATP channels, leptin inhibits insulin secretion by PI3K-induced activation of phosphodiesterase 3B (PDE3B), which in turn decreases cAMP levels in rat pancreatic islets and HIT-T15 cells (Zhao et al. 1998). This would negatively affect the insulin secretion dependent on cAMP/protein kinase A (PKA). The physiological importance of this signaling mechanism is evidenced by the fact that leptin can suppress glucagon-like peptide 1-stimulated insulin secretion (Fehmann et al. 1997a,b, Zhao et al. 1998). Similarly, leptin inhibits insulin secretion in INS-1 cells in conditions of elevated cAMP levels (Ahren & Havel 1999). Moreover, leptin inhibits the phospholipase C (PLC)/protein kinase C (PKC) pathway in islets from ob/ob mice, decreasing insulin secretion when this route is activated (Chen et al. 1997). Therefore, several mechanisms may account for the inhibitory role of leptin in β-cell secretion (Fig. 3).

Figure 3
Figure 3

The stimulus–secretion coupling of pancreatic β-cells involves several steps. Glucose is incorporated into the cytosol through GLUT-2 transporters. Glucose mitochondrial metabolism allows for an increase of the intracellular ATP/ADP ratio. This increase closes KATP channels, inducing the plasma membrane depolarization and subsequent activation of VDCCs, which leads to an intracellular Ca2+ influx that triggers exocytosis. Leptin inhibits glucose transport through GLUT-2, and, thus, it would inhibit the subsequent events in the stimulus–secretion coupling. Leptin also activates PI3K-dependent reorganization of the actin cytoskeleton, leading to the opening of KATP channels and to plasma membrane hyperpolarization. Additionally, PI3K-dependent activation of PDE3B by leptin reduces cAMP levels, inhibiting the PKA pathway, which is involved in the regulation of Ca2+ channels and exocytosis. Leptin can also inhibit the PLC/PKC pathway.

Citation: Journal of Molecular Endocrinology 49, 1; 10.1530/JME-12-0025

Effect of leptin on insulin gene expression

Numerous studies have shown that leptin inhibits insulin gene expression. At 0.625–10 nM, leptin decreases proinsulin gene expression in the β-cell lines β-TC6, HIT-T15, and INS-1 after incubation with the hormone for 16–40 h (Kulkarni et al. 1997, Seufert et al. 1999a, Tsiotra et al. 2001). Analysis of proinsulin mRNA levels revealed a decrease in isolated rat islets after incubation with 1–10 nM leptin (Kulkarni et al. 1997, Pallett et al. 1997). This effect has also been observed in ob/ob mice treated in vivo with leptin and in in vitro experiments with isolated islets from these animals (Seufert et al. 1999a). In humans, in vitro experiments demonstrated that incubation of pancreatic islets with 6.25 nM leptin for 48 h also reduces proinsulin mRNA levels (Seufert et al. 1999b). This effect was observed at 11.2 mM glucose but not at 5.6 mM, indicating that leptin inhibition was dependent on stimulatory glucose levels. Consistent with these findings, leptin reduces proinsulin expression at 25 mM glucose but not at lower concentrations in INS-1 cells (Seufert et al. 1999a). Similarly, leptin inhibition of proinsulin mRNA transcription is higher at 16.7 mM glucose than at 7 mM in HIT-T15 cells (Tsiotra et al. 2001). Thus, it seems that leptin depends on stimulatory glucose concentrations to exert its action on insulin transcription.

This inhibitory function of leptin in the β-cell is mediated by the activation of JAK/STAT signaling. After the phosphorylation of JAK2 proteins, this pathway involves the recruitment of STAT proteins that work as transcriptional factors in the nucleus. It has been shown that leptin activates the STAT3 protein and promotes DNA binding of STAT proteins in nuclear extracts from RINm5F cells and isolated rat islets (Morton et al. 2011). In INS-1 cells, it was reported that STAT5b was involved in leptin-mediated repression of the rat insulin I gene promoter (Seufert et al. 1999a). More recently, this signaling pathway has been further characterized (Laubner et al. 2005). Although STAT1, -3, -5b, and -6 are present in INS-1 cells, it seems that leptin-mediated activation of JAK2 recruits basically STAT3 and -5b. Interestingly, it was shown that the inhibitory effect of leptin on insulin gene expression was not mediated by direct interaction of STAT3 or -5b with the proinsulin promoter (Laubner et al. 2005). By contrast, leptin-induced suppressor of cytokine signaling 3 (SOCS3) expression by STAT-dependent mechanisms was found to be responsible for the inhibition of the rat insulin I gene promoter activity (Laubner et al. 2005; Fig. 4). Thus, SOCS3 has another function in the pancreatic β-cell different from the well-known role as a negative regulator of the JAK/STAT pathway (Fruhbeck 2006). Given that leptin also increases SOCS3 expression in isolated human pancreatic islets and in islets from ob/ob mice treated in vivo, it seems that this mechanism may be general for various species (Laubner et al. 2005). Consistent with these findings, SOCS3 mRNA is decreased and proinsulin mRNA is increased in KO mice with a pancreas-specific disruption of the leptin receptor (Morioka et al. 2007).

Figure 4
Figure 4

In the pancreatic β-cell, leptin induces the activation of STAT3 and STAT5B, which migrate to the nucleus and induce the expression of SOCS3. Although SOCS3 is a well-known inhibitor of the JAK/STAT pathway, in the β-cell it inhibits the expression of proinsulin.

Citation: Journal of Molecular Endocrinology 49, 1; 10.1530/JME-12-0025

Regulation of β-cell mass by leptin

The regulation of β-cell mass is essential for the compensatory response of the endocrine pancreas to situations of increased insulin demand such as obesity (Sachdeva & Stoffers 2009). Cell mass remodeling is the result of several processes, which include proliferation, neogenesis, cell size, and apoptosis. Several studies have reported leptin effects in the majority of these processes (Table 1). Experiments about the leptin effect on proliferation were initially performed in β-cell lines. Leptin mediates a proliferative response in RINm5F at concentrations of about 100 nM (Islam et al. 1997). In MIN-6 cells, this hormone at 1–10 nM increased proliferation as well through activation of the MAPK pathway (Tanabe et al. 1997). This proliferative response has been also observed in fetal islet cells and it has been postulated that it might have a role in β-cell mass at birth (Islam et al. 2000). Conversely, no proliferative action of leptin has been found in experiments with islets from adult rats (Okuya et al. 2001). Recent studies with disruption of the leptin receptor either in the pancreas (Morioka et al. 2007) or in β-cells and hypothalamus (Covey et al. 2006) indicate that leptin may have a negative role in β-cell mass expansion, since the average size of the islets from these KO mice was found to be increased. In one of these studies, no modification of proliferation was observed (Morioka et al. 2007). Instead, the enhanced islet mass in these KO mice was attributed to augmented β-cell size due to increased activity of p70S6 kinase and PKB. Thus, these latter studies using KO mice indicate that leptin may negatively contribute to β-cell mass expansion.

Table 1

Regulation of β-cell mass by leptin

Effectβ-cell modelPathway/signaling moleculesReference
Proliferative RINm5F cellsc-fosIslam et al. (1997)
Proliferative MIN-6 cellsMAPKTanabe et al. (1997)
Proliferative Rat fetal islet cellsc-fosIslam et al. (2000)
No proliferative effect Rat pancreatic isletsOkuya et al. (2001)
Increased islet area KO mice with disruption of leptin  receptor in hypothalamus and  β-cellsCovey et al. (2006)
Increased islet area,  increased cell size,  no proliferation KO mice with disruption of leptin  receptor in pancreasp70S6 kinase, PKBMorioka et al. (2007)
Antiapoptotic Rat pancreatic islets↓ Triglyceride content, ↓ iNOSOkuya et al. (2001)
Antiapoptotic Gene transfer of leptin receptor in  islets from Zucker diabetic rats↓ Triglyceride content, ↓ iNOS, ↓ NOWang et al. (1998a,b)
Antiapoptotic Islets from Zucker diabetic rats↑ Bcl2Shimabukuro et al. (1998)
Antiapoptotic BRIN-BD11 cells↑ Bcl2, ↓ BaxBrown & Dunmore (2007)
Proapoptotic INS-1 cells and human islets JNKMaedler et al. (2008)
Proapoptotic Human islets↓ IL1 receptor antagonist expressionMaedler et al. (2004)
Proapoptotic RINm5F↑ Caspase activity, ↑ expression of  inflammation-related genesHekerman et al. (2007)

Both protective and deleterious effects have been attributed to leptin (Table 1). At 1–5 nM, leptin increases the viability of rat pancreatic islets by suppressing apoptosis, a process that was associated with decreases in both triglyceride content and inducible NO synthase (iNOS) expression, which probably would decrease the levels of NO as a proapoptotic factor (Okuya et al. 2001). Similarly, gene transfer of the leptin receptor to obese Zucker diabetic rats led to reduced triglyceride content, iNOS expression, and NO production when their pancreatic islets were incubated with leptin, indicative of a protective effect of this hormone against lipoapoptosis (Wang et al. 1998a,b). Consistent with this protective action, leptin modulates the expression of the antiapoptotic gene β-cell leukemia 2 gene product (Bcl2), preventing against fatty acid-induced apoptosis (Shimabukuro et al. 1998). Likewise, leptin protects from apoptosis in the β-cell line BRIN-BD11 by increasing BCL2 and decreasing Bcl2 associated X protein (BAX; Brown & Dunmore 2007). On the contrary, other studies have shown leptin deleterious effects in the pancreatic β-cell. In human β-cells and INS-1 cells, chronically elevated concentrations of glucose (33.3 mM) and leptin (10 nM) induce apoptosis through activation of the JNK pathway (Maedler et al. 2008). Additionally, chronic exposure of human β-cells to leptin triggers apoptotic events by decreasing the expression of interleukin 1 (IL1) receptor antagonist and enhancing the release of IL1B (Maedler et al. 2004). Activation of the leptin receptor in RINm5F insulinoma cells also led to the upregulation of numerous genes related to inflammation as well as an increase of caspase proteolytic activity (Hekerman et al. 2007). Thus, given the diversity of effects observed in the islet, the role of leptin in the regulation of β-cell mass still deserves much attention.

Leptin resistance

Although leptin reduces food intake and body weight, obesity is characterized by high plasma leptin levels. In this regard, several studies have shown that attenuated leptin signaling is present in this metabolic disorder. This leptin resistance would explain why high leptin levels fail to induce the expected decreasing effects on feeding and body weight that would mitigate obesity. Several factors have been shown to mediate leptin resistance at the central level: impaired leptin transport in the blood–brain barrier, endoplasmic reticulum stress, and impaired leptin signaling, among others (Zhang et al. 2008, Morris & Rui 2009, Ozcan et al. 2009). Most of these alterations have been observed in models of diet-induced obesity. Several studies have also shown that attenuated leptin signaling in obesity models is related to increased levels or activity of SOCS3, protein tyrosine phosphatase 1B (PTP1B), and/or T-cell protein tyrosine phosphatase (TCPTP; Myers et al. 2010). Both proteins work as negative regulators of leptin-induced activation of the JAK/STAT pathway (Morris & Rui 2009). In addition to central leptin resistance, several studies on obesity models have observed attenuated leptin signaling in peripheral tissues (Prpic et al. 2003, Lam et al. 2006, Steinberg et al. 2006, Nave et al. 2008). In most cases, an increase in PTP1B or SOCS3 levels was associated with this attenuated response to leptin. In the case of the endocrine pancreas, it has been proposed that leptin resistance in the β-cell may alter its function and could contribute to diabetes in obese individuals (Seufert 2004, Covey et al. 2006, Morioka et al. 2007). Since leptin signaling in the pancreatic β-cell triggers similar pathways as those activated in the hypothalamus or other tissues, it would be interesting to explore whether leptin resistance occurs in the β-cell during obesity and the mechanisms involved. For instance, although SOCS3 and PTP1B are implicated in several functions in the islet (Karlsen et al. 2001, Kushner et al. 2004, Laubner et al. 2005), their role in attenuated leptin signaling during obesity has not yet been studied in the pancreatic β-cell.

Conclusions

Among other functions, leptin modulates glucose homeostasis through central and peripheral actions. While several peripheral organs such as muscle, adipose tissue, and liver may participate in this process, the pancreatic β-cell is also an important player regulated by leptin. Numerous studies using different approaches and animal models have shown that leptin inhibits insulin gene expression and insulin secretion. Additionally, leptin produces distinct effects on proliferation, apoptosis, and cell size depending on the studied model. In this regard, much research is required to further determine the role of leptin in β-cell mass. Moreover, some studies have reported the effects of leptin on human β-cells that are different from those observed in animal models, particularly about the protective or deleterious actions of leptin. Thus, additional data will be necessary to contrast the function of leptin in animals and humans and to dissect the different roles. All this information is necessary to have a better understanding of the role of leptin in the β-cell and in the regulation of glucose homeostasis, as well as in the communication between the endocrine pancreas and the adipose tissue.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by grants from the Ministerio de Ciencia e Innovación (grant numbers BFU2010-21773, BFU2011-28358) and Generalitat Valenciana (grant number PROMETEO/2011/080). CIBERDEM is an initiative of the Instituto de Salud Carlos III.

References

  • AhrenBHavelPJ1999Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells). American Journal of Physiology277R959R966.

    • Search Google Scholar
    • Export Citation
  • BertiLKellererMCappEHaringHU1997Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes: evidence for a P13-kinase mediated effect. Diabetologia40606609. doi:10.1007/s001250050722.

    • Search Google Scholar
    • Export Citation
  • BrownJEDunmoreSJ2007Leptin decreases apoptosis and alters BCL-2: Bax ratio in clonal rodent pancreatic β-cells. Diabetes/Metabolism Research and Reviews23497502. doi:10.1002/dmrr.726.

    • Search Google Scholar
    • Export Citation
  • BrownJEThomasSDigbyJEDunmoreSJ2002Glucose induces and leptin decreases expression of uncoupling protein-2 mRNA in human islets. FEBS Letters513189192. doi:10.1016/S0014-5793(02)02296-2.

    • Search Google Scholar
    • Export Citation
  • CasesJAGabrielyIMaXHYangXMMichaeliTFleischerNRossettiLBarzilaiN2001Physiological increase in plasma leptin markedly inhibits insulin secretion in vivo. Diabetes50348352. doi:10.2337/diabetes.50.2.348.

    • Search Google Scholar
    • Export Citation
  • CeddiaRBLopesGSouzaHMBorba-MuradGRWilliamWNJrBazotteRBCuriR1999aAcute effects of leptin on glucose metabolism of in situ rat perfused livers and isolated hepatocytes. International Journal of Obesity and Related Metabolic Disorders2312071212. doi:10.1038/sj.ijo.0801095.

    • Search Google Scholar
    • Export Citation
  • CeddiaRBWilliamWNJrCuriR1999bComparing effects of leptin and insulin on glucose metabolism in skeletal muscle: evidence for an effect of leptin on glucose uptake and decarboxylation. International Journal of Obesity and Related Metabolic Disorders237582. doi:10.1038/sj.ijo.0800762.

    • Search Google Scholar
    • Export Citation
  • ChenNGSwickAGRomsosDR1997Leptin constrains acetylcholine-induced insulin secretion from pancreatic islets of ob/ob mice. Journal of Clinical Investigation10011741179. doi:10.1172/JCI119629.

    • Search Google Scholar
    • Export Citation
  • ChinookoswongNWangJLShiZQ1999Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes4814871492. doi:10.2337/diabetes.48.7.1487.

    • Search Google Scholar
    • Export Citation
  • CoppariRIchinoseMLeeCEPullenAEKennyCDMcGovernRATangVLiuSMLudwigTChuaSCJr2005The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. Cell Metabolism16372. doi:10.1016/j.cmet.2004.12.004.

    • Search Google Scholar
    • Export Citation
  • CoveySDWidemanRDMcDonaldCUnniappanSHuynhFAsadiASpeckMWebberTChuaSCKiefferTJ2006The pancreatic β cell is a key site for mediating the effects of leptin on glucose homeostasis. Cell Metabolism4291302. doi:10.1016/j.cmet.2006.09.005.

    • Search Google Scholar
    • Export Citation
  • CummingsBPBettaiebAGrahamJLStanhopeKLDillRMortonGJHajFGHavelPJ2011Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. PNAS1081467014675. doi:10.1073/pnas.1107163108.

    • Search Google Scholar
    • Export Citation
  • DenrocheHCLeviJWidemanRDSequeiraRMHuynhFKCoveySDKiefferTJ2011Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes6014141423. doi:10.2337/db10-0958.

    • Search Google Scholar
    • Export Citation
  • DubucPU1976The development of obesity, hyperinsulinemia, and hyperglycemia in ob/ob mice. Metabolism2515671574. doi:10.1016/0026-0495(76)90109-8.

    • Search Google Scholar
    • Export Citation
  • EmilssonVLiuYLCawthorneMAMortonNMDavenportM1997Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes46313316. doi:10.2337/diabetes.46.2.313.

    • Search Google Scholar
    • Export Citation
  • FehmannHCBodeHPEbertTKarlAGokeB1997aInteraction of GLP-I and leptin at rat pancreatic B-cells: effects on insulin secretion and signal transduction. Hormone and Metabolic Research29572576. doi:10.1055/s-2007-979103.

    • Search Google Scholar
    • Export Citation
  • FehmannHCPeiserCBodeHPStammMStaatsPHedetoftCLangREGokeB1997bLeptin: a potent inhibitor of insulin secretion. Peptides1812671273. doi:10.1016/S0196-9781(97)00135-6.

    • Search Google Scholar
    • Export Citation
  • FruhbeckG2006Intracellular signalling pathways activated by leptin. Biochemical Journal393720. doi:10.1042/BJ20051578.

  • FujikawaTChuangJCSakataIRamadoriGCoppariR2010Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. PNAS1071739117396. doi:10.1073/pnas.1008025107.

    • Search Google Scholar
    • Export Citation
  • GenuthSMPrzybylskiRJRosenbergDM1971Insulin resistance in genetically obese, hyperglycemic mice. Endocrinology8812301238. doi:10.1210/endo-88-5-1230.

    • Search Google Scholar
    • Export Citation
  • GermanJPThalerJPWisseBEOh-ISSarrufDAMatsenMEFischerJDTaborskyGJJrSchwartzMWMortonGJ2011Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology152394404. doi:10.1210/en.2010-0890.

    • Search Google Scholar
    • Export Citation
  • GraySLDonaldCJethaACoveySDKiefferTJ2010Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic β-cell leptin signaling. Endocrinology15141784186. doi:10.1210/en.2010-0102.

    • Search Google Scholar
    • Export Citation
  • HarveyJHardySCIrvingAJAshfordML2000Leptin activation of ATP-sensitive K+ (KATP) channels in rat CRI-G1 insulinoma cells involves disruption of the actin cytoskeleton. Journal of Physiology52795107. doi:10.1111/j.1469-7793.2000.00095.x.

    • Search Google Scholar
    • Export Citation
  • HekermanPZeidlerJKorfmacherSBamberg-LemperSKnobelspiesHZabeauLTavernierJBeckerW2007Leptin induces inflammation-related genes in RINm5F insulinoma cells. BMC Molecular Biology841doi:10.1186/1471-2199-8-41.

    • Search Google Scholar
    • Export Citation
  • HillJWEliasCFFukudaMWilliamsKWBerglundEDHollandWLChoYRChuangJCXuYChoiM2010Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metabolism11286297. doi:10.1016/j.cmet.2010.03.002.

    • Search Google Scholar
    • Export Citation
  • HuoLGamberKGreeleySSilvaJHuntoonNLengXHBjorbaekC2009Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metabolism9537547. doi:10.1016/j.cmet.2009.05.003.

    • Search Google Scholar
    • Export Citation
  • IslamMSMortonNMHanssonAEmilssonV1997Rat insulinoma-derived pancreatic β-cells express a functional leptin receptor that mediates a proliferative response. Biochemical and Biophysical Research Communications238851855. doi:10.1006/bbrc.1997.7399.

    • Search Google Scholar
    • Export Citation
  • IslamMSSjoholmAEmilssonV2000Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells. International Journal of Obesity and Related Metabolic Disorders2412461253. doi:10.1038/sj.ijo.0801370.

    • Search Google Scholar
    • Export Citation
  • KarlsenAERonnSGLindbergKJohannesenJGalsgaardEDPociotFNielsenJHMandrup-PoulsenTNerupJBillestrupN2001Suppressor of cytokine signaling 3 (SOCS-3) protects β-cells against interleukin-1β- and interferon-gamma-mediated toxicity. PNAS981219112196. doi:10.1073/pnas.211445998.

    • Search Google Scholar
    • Export Citation
  • KiefferTJHellerRSHabenerJF1996Leptin receptors expressed on pancreatic β-cells. Biochemical and Biophysical Research Communications224522527. doi:10.1006/bbrc.1996.1059.

    • Search Google Scholar
    • Export Citation
  • KiefferTJHellerRSLeechCAHolzGGHabenerJF1997Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic β-cells. Diabetes4610871093. doi:10.2337/diabetes.46.6.1087.

    • Search Google Scholar
    • Export Citation
  • KojimaSAsakawaAAmitaniHSakoguchiTUenoNInuiAKalraSP2009Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice. Peptides30962966. doi:10.1016/j.peptides.2009.01.007.

    • Search Google Scholar
    • Export Citation
  • KuehnenPLaubnerKRaileKSchoflCJakobFPilzIPathGSeufertJ2011Protein phosphatase 1 (PP-1)-dependent inhibition of insulin secretion by leptin in INS-1 pancreatic β-cells and human pancreatic islets. Endocrinology15218001808. doi:10.1210/en.2010-1094.

    • Search Google Scholar
    • Export Citation
  • KulkarniRNWangZLWangRMHurleyJDSmithDMGhateiMAWithersDJGardinerJVBaileyCJBloomSR1997Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. Journal of Clinical Investigation10027292736. doi:10.1172/JCI119818.

    • Search Google Scholar
    • Export Citation
  • KushnerJAHajFGKlamanLDDowMAKahnBBNeelBGWhiteMF2004Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. Diabetes536166. doi:10.2337/diabetes.53.1.61.

    • Search Google Scholar
    • Export Citation
  • LamNTCheungATRiedelMJLightPECheesemanCIKiefferTJ2004Leptin reduces glucose transport and cellular ATP levels in INS-1 β-cells. Journal of Molecular Endocrinology32415424. doi:10.1677/jme.0.0320415.

    • Search Google Scholar
    • Export Citation
  • LamNTCoveySDLewisJTOosmanSWebberTHsuECCheungATKiefferTJ2006Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver. Journal of Molecular Endocrinology36163174. doi:10.1677/jme.1.01937.

    • Search Google Scholar
    • Export Citation
  • LaubnerKKiefferTJLamNTNiuXJakobFSeufertJ2005Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic β-cells. Diabetes5434103417. doi:10.2337/diabetes.54.12.3410.

    • Search Google Scholar
    • Export Citation
  • Leclercq-MeyerVMalaisseWJ1998Failure of human and mouse leptin to affect insulin, glucagon and somatostatin secretion by the perfused rat pancreas at physiological glucose concentration. Molecular and Cellular Endocrinology141111118. doi:10.1016/S0303-7207(98)00087-2.

    • Search Google Scholar
    • Export Citation
  • LeeYHMagkosFMantzorosCSKangES2011Effects of leptin and adiponectin on pancreatic β-cell function. Metabolism6016641672. doi:10.1016/j.metabol.2011.04.008.

    • Search Google Scholar
    • Export Citation
  • LeviJGraySLSpeckMHuynhFKBabichSLGibsonWTKiefferTJ2011Acute disruption of leptin signaling in vivo leads to increased insulin levels and insulin resistance. Endocrinology15233853395. doi:10.1210/en.2011-0185.

    • Search Google Scholar
    • Export Citation
  • LicinioJMantzorosCNegraoABCizzaGWongMLBongiornoPBChrousosGPKarpBAllenCFlierJS1997Human leptin levels are pulsatile and inversely related to pituitary–adrenal function. Nature Medicine3575579. doi:10.1038/nm0597-575.

    • Search Google Scholar
    • Export Citation
  • LupiRMarchettiPMaffeiMDel GuerraSBenziLMarselliLBertaccaANavalesiR1999Effects of acute or prolonged exposure to human leptin on isolated human islet function. Biochemical and Biophysical Research Communications256637641. doi:10.1006/bbrc.1999.0384.

    • Search Google Scholar
    • Export Citation
  • MaedlerKSergeevPEhsesJAMatheZBoscoDBerneyTDayerJMReineckeMHalbanPADonathMY2004Leptin modulates β cell expression of IL-1 receptor antagonist and release of IL-1β in human islets. PNAS10181388143. doi:10.1073/pnas.0305683101.

    • Search Google Scholar
    • Export Citation
  • MaedlerKSchulthessFTBielmanCBerneyTBonnyCPrentkiMDonathMYRoduitR2008Glucose and leptin induce apoptosis in human β-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases. FASEB Journal2219051913. doi:10.1096/fj.07-101824.

    • Search Google Scholar
    • Export Citation
  • MantzorosCSMagkosFBrinkoetterMSienkiewiczEDardenoTAKimSYHamnvikOPKoniarisA2011Leptin in human physiology and pathophysiology. American Journal of Physiology. Endocrinology and Metabolism301E567E584. doi:10.1152/ajpendo.00315.2011.

    • Search Google Scholar
    • Export Citation
  • MeyerCRobsonDRackovskyNNadkarniVGerichJ1997Role of the kidney in human leptin metabolism. American Journal of Physiology273E903E907.

  • MoriokaTAsilmazEHuJDishingerJFKurpadAJEliasCFLiHElmquistJKKennedyRTKulkarniRN2007Disruption of leptin receptor expression in the pancreas directly affects β cell growth and function in mice. Journal of Clinical Investigation11728602868. doi:10.1172/JCI30910.

    • Search Google Scholar
    • Export Citation
  • MorrisDLRuiL2009Recent advances in understanding leptin signaling and leptin resistance. American Journal of Physiology. Endocrinology and Metabolism297E1247E1259. doi:10.1152/ajpendo.00274.2009.

    • Search Google Scholar
    • Export Citation
  • MortonGJSchwartzMW2011Leptin and the central nervous system control of glucose metabolism. Physiological Reviews91389411. doi:10.1152/physrev.00007.2010.

    • Search Google Scholar
    • Export Citation
  • MortonGJKaiyalaKJFisherJDOgimotoKSchwartzMWWisseBE2011Identification of a physiological role for leptin in the regulation of ambulatory activity and wheel running in mice. American Journal of Physiology. Endocrinology and Metabolism300E392E401. doi:10.1152/ajpendo.00546.2010.

    • Search Google Scholar
    • Export Citation
  • MyersMGJrLeibelRLSeeleyRJSchwartzMW2010Obesity and leptin resistance: distinguishing cause from effect. Trends in Endocrinology and Metabolism21643651. doi:10.1016/j.tem.2010.08.002.

    • Search Google Scholar
    • Export Citation
  • NaitoMFujikuraJEbiharaKMiyanagaFYokoiHKusakabeTYamamotoYSonCMukoyamaMHosodaK2011Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice. Diabetes6022652273. doi:10.2337/db10-1795.

    • Search Google Scholar
    • Export Citation
  • NaveHMuellerGSiegmundBJacobsRStrohTSchuelerUHopfeMBehrendtPBuchenauerTPabstR2008Resistance of Janus kinase-2 dependent leptin signaling in natural killer (NK) cells: a novel mechanism of NK cell dysfunction in diet-induced obesity. Endocrinology14933703378. doi:10.1210/en.2007-1516.

    • Search Google Scholar
    • Export Citation
  • NingKMillerLCLaidlawHABurgessLAPereraNMDownesCPLeslieNRAshfordML2006A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic β-cells. EMBO Journal2523772387. doi:10.1038/sj.emboj.7601118.

    • Search Google Scholar
    • Export Citation
  • OkuyaSTanabeKTanizawaYOkaY2001Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis. Endocrinology14248274830. doi:10.1210/en.142.11.4827.

    • Search Google Scholar
    • Export Citation
  • OzcanLErginASLuAChungJSarkarSNieDMyersMGJrOzcanU2009Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metabolism93551. doi:10.1016/j.cmet.2008.12.004.

    • Search Google Scholar
    • Export Citation
  • PallettALMortonNMCawthorneMAEmilssonV1997Leptin inhibits insulin secretion and reduces insulin mRNA levels in rat isolated pancreatic islets. Biochemical and Biophysical Research Communications238267270. doi:10.1006/bbrc.1997.7274.

    • Search Google Scholar
    • Export Citation
  • ParkSAhnISKimDS2010Central infusion of leptin improves insulin resistance and suppresses β-cell function, but not β-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model. Life Sciences86854862. doi:10.1016/j.lfs.2010.03.021.

    • Search Google Scholar
    • Export Citation
  • PelleymounterMACullenMJBakerMBHechtRWintersDBooneTCollinsF1995Effects of the obese gene product on body weight regulation in ob/ob mice. Science269540543. doi:10.1126/science.7624776.

    • Search Google Scholar
    • Export Citation
  • PerezCFernandez-GalazCFernandez-AgulloTArribasCAndresARosMCarrascosaJM2004Leptin impairs insulin signaling in rat adipocytes. Diabetes53347353. doi:10.2337/diabetes.53.2.347.

    • Search Google Scholar
    • Export Citation
  • PoitoutVRouaultCGuerre-MilloMBriaudIReachG1998Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans. Endocrinology139822826. doi:10.1210/en.139.3.822.

    • Search Google Scholar
    • Export Citation
  • PrpicVWatsonPMFramptonICSabolMAJezekGEGettysTW2003Differential mechanisms and development of leptin resistance in A/J versus C57BL/6J mice during diet-induced obesity. Endocrinology14411551163. doi:10.1210/en.2002-220835.

    • Search Google Scholar
    • Export Citation
  • SachdevaMMStoffersDA2009Minireview: meeting the demand for insulin: molecular mechanisms of adaptive postnatal β-cell mass expansion. Molecular Endocrinology23747758. doi:10.1210/me.2008-0400.

    • Search Google Scholar
    • Export Citation
  • SchwartzMWBaskinDGBukowskiTRKuijperJLFosterDLasserGPrunkardDEPorteDJrWoodsSCSeeleyRJ1996Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes45531535. doi:10.2337/diabetes.45.4.531.

    • Search Google Scholar
    • Export Citation
  • SeufertJ2004Leptin effects on pancreatic β-cell gene expression and function. Diabetes53 (Suppl 1) S152S158. doi:10.2337/diabetes.53.2007.S152.

    • Search Google Scholar
    • Export Citation
  • SeufertJKiefferTJHabenerJF1999aLeptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice. PNAS96674679. doi:10.1073/pnas.96.2.674.

    • Search Google Scholar
    • Export Citation
  • SeufertJKiefferTJLeechCAHolzGGMoritzWRicordiCHabenerJF1999bLeptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. Journal of Clinical Endocrinology and Metabolism84670676. doi:10.1210/jc.84.2.670.

    • Search Google Scholar
    • Export Citation
  • ShimabukuroMWangMYZhouYTNewgardCBUngerRH1998Protection against lipoapoptosis of β cells through leptin-dependent maintenance of Bcl-2 expression. PNAS9595589561. doi:10.1073/pnas.95.16.9558.

    • Search Google Scholar
    • Export Citation
  • ShimomuraIHammerREIkemotoSBrownMSGoldsteinJL1999Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature4017376. doi:10.1038/43448.

    • Search Google Scholar
    • Export Citation
  • SteinbergGRWattMJFamBCProiettoJAndrikopoulosSAllenAMFebbraioMAKempBE2006Ciliary neurotrophic factor suppresses hypothalamic AMP-kinase signaling in leptin-resistant obese mice. Endocrinology14739063914. doi:10.1210/en.2005-1587.

    • Search Google Scholar
    • Export Citation
  • TanabeKOkuyaSTanizawaYMatsutaniAOkaY1997Leptin induces proliferation of pancreatic β cell line MIN6 through activation of mitogen-activated protein kinase. Biochemical and Biophysical Research Communications241765768. doi:10.1006/bbrc.1997.7894.

    • Search Google Scholar
    • Export Citation
  • TanizawaYOkuyaSIshiharaHAsanoTYadaTOkaY1997Direct stimulation of basal insulin secretion by physiological concentrations of leptin in pancreatic β cells. Endocrinology13845134516. doi:10.1210/en.138.10.4513.

    • Search Google Scholar
    • Export Citation
  • TsiotraPCTsigosCRaptisSA2001TNFalpha and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells. International Journal of Obesity and Related Metabolic Disorders2510181026. doi:10.1038/sj.ijo.0801657.

    • Search Google Scholar
    • Export Citation
  • WangMYKoyamaKShimabukuroMMangelsdorfDNewgardCBUngerRH1998aOverexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion. PNAS951192111926. doi:10.1073/pnas.95.20.11921.

    • Search Google Scholar
    • Export Citation
  • WangMYKoyamaKShimabukuroMNewgardCBUngerRH1998bOB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype. PNAS95714718. doi:10.1073/pnas.95.2.714.

    • Search Google Scholar
    • Export Citation
  • WangMYChenLClarkGOLeeYStevensRDIlkayevaORWennerBRBainJRCharronMJNewgardCB2010Leptin therapy in insulin-deficient type I diabetes. PNAS10748134819. doi:10.1073/pnas.0909422107.

    • Search Google Scholar
    • Export Citation
  • YuXParkBHWangMYWangZVUngerRH2008Making insulin-deficient type 1 diabetic rodents thrive without insulin. PNAS1051407014075. doi:10.1073/pnas.0806993105.

    • Search Google Scholar
    • Export Citation
  • ZhangXZhangGZhangHKarinMBaiHCaiD2008Hypothalamic IKKβ/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell1356173. doi:10.1016/j.cell.2008.07.043.

    • Search Google Scholar
    • Export Citation
  • ZhaoAZBornfeldtKEBeavoJA1998Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. Journal of Clinical Investigation102869873. doi:10.1172/JCI3920.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 3663 1063 74
PDF Downloads 642 280 15
  • View in gallery

    The leptin receptor has six isoforms obtained by alternative splicing, which are designated ObRa, ObRb, ObRc, ObRd, ObRe, and ObRf. While the extracellular domain is common for all of these isoforms, the intracellular domain differs from one variant to another. The number below each form indicates the number of amino acids characteristic of each isoform. The box 1 motif is required for JAK interaction and activation. However, only the long form (ObRb) contains motifs for the complete activation of the JAK/STAT pathway. Three tyrosine residues, whose phosphorylation is important for leptin signaling, are indicated in ObRb: Y985 interacts with the SH2-containing protein tyrosine phosphatase 2, Y1077 with STAT5, and Y1138 with STAT3.

  • View in gallery

    Leptin binding to its receptor activates the associated JAK-2 tyrosine kinase, which subsequently phosphorylates intracellular tyrosine residues of the receptor. This leads to the activation of STAT3, which dimerizes and migrates to the nucleus, where it works as a transcription factor, promoting the expression of genes like neuropeptide Y (NPY). STAT3 also induces the expression of SOCS3, a protein that acts as a negative regulator of the JAK/STAT pathway. Likewise, PTP1B is another protein that negatively regulates the JAK/STAT route.

  • View in gallery

    The stimulus–secretion coupling of pancreatic β-cells involves several steps. Glucose is incorporated into the cytosol through GLUT-2 transporters. Glucose mitochondrial metabolism allows for an increase of the intracellular ATP/ADP ratio. This increase closes KATP channels, inducing the plasma membrane depolarization and subsequent activation of VDCCs, which leads to an intracellular Ca2+ influx that triggers exocytosis. Leptin inhibits glucose transport through GLUT-2, and, thus, it would inhibit the subsequent events in the stimulus–secretion coupling. Leptin also activates PI3K-dependent reorganization of the actin cytoskeleton, leading to the opening of KATP channels and to plasma membrane hyperpolarization. Additionally, PI3K-dependent activation of PDE3B by leptin reduces cAMP levels, inhibiting the PKA pathway, which is involved in the regulation of Ca2+ channels and exocytosis. Leptin can also inhibit the PLC/PKC pathway.

  • View in gallery

    In the pancreatic β-cell, leptin induces the activation of STAT3 and STAT5B, which migrate to the nucleus and induce the expression of SOCS3. Although SOCS3 is a well-known inhibitor of the JAK/STAT pathway, in the β-cell it inhibits the expression of proinsulin.

  • AhrenBHavelPJ1999Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells). American Journal of Physiology277R959R966.

    • Search Google Scholar
    • Export Citation
  • BertiLKellererMCappEHaringHU1997Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes: evidence for a P13-kinase mediated effect. Diabetologia40606609. doi:10.1007/s001250050722.

    • Search Google Scholar
    • Export Citation
  • BrownJEDunmoreSJ2007Leptin decreases apoptosis and alters BCL-2: Bax ratio in clonal rodent pancreatic β-cells. Diabetes/Metabolism Research and Reviews23497502. doi:10.1002/dmrr.726.

    • Search Google Scholar
    • Export Citation
  • BrownJEThomasSDigbyJEDunmoreSJ2002Glucose induces and leptin decreases expression of uncoupling protein-2 mRNA in human islets. FEBS Letters513189192. doi:10.1016/S0014-5793(02)02296-2.

    • Search Google Scholar
    • Export Citation
  • CasesJAGabrielyIMaXHYangXMMichaeliTFleischerNRossettiLBarzilaiN2001Physiological increase in plasma leptin markedly inhibits insulin secretion in vivo. Diabetes50348352. doi:10.2337/diabetes.50.2.348.

    • Search Google Scholar
    • Export Citation
  • CeddiaRBLopesGSouzaHMBorba-MuradGRWilliamWNJrBazotteRBCuriR1999aAcute effects of leptin on glucose metabolism of in situ rat perfused livers and isolated hepatocytes. International Journal of Obesity and Related Metabolic Disorders2312071212. doi:10.1038/sj.ijo.0801095.

    • Search Google Scholar
    • Export Citation
  • CeddiaRBWilliamWNJrCuriR1999bComparing effects of leptin and insulin on glucose metabolism in skeletal muscle: evidence for an effect of leptin on glucose uptake and decarboxylation. International Journal of Obesity and Related Metabolic Disorders237582. doi:10.1038/sj.ijo.0800762.

    • Search Google Scholar
    • Export Citation
  • ChenNGSwickAGRomsosDR1997Leptin constrains acetylcholine-induced insulin secretion from pancreatic islets of ob/ob mice. Journal of Clinical Investigation10011741179. doi:10.1172/JCI119629.

    • Search Google Scholar
    • Export Citation
  • ChinookoswongNWangJLShiZQ1999Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. Diabetes4814871492. doi:10.2337/diabetes.48.7.1487.

    • Search Google Scholar
    • Export Citation
  • CoppariRIchinoseMLeeCEPullenAEKennyCDMcGovernRATangVLiuSMLudwigTChuaSCJr2005The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. Cell Metabolism16372. doi:10.1016/j.cmet.2004.12.004.

    • Search Google Scholar
    • Export Citation
  • CoveySDWidemanRDMcDonaldCUnniappanSHuynhFAsadiASpeckMWebberTChuaSCKiefferTJ2006The pancreatic β cell is a key site for mediating the effects of leptin on glucose homeostasis. Cell Metabolism4291302. doi:10.1016/j.cmet.2006.09.005.

    • Search Google Scholar
    • Export Citation
  • CummingsBPBettaiebAGrahamJLStanhopeKLDillRMortonGJHajFGHavelPJ2011Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. PNAS1081467014675. doi:10.1073/pnas.1107163108.

    • Search Google Scholar
    • Export Citation
  • DenrocheHCLeviJWidemanRDSequeiraRMHuynhFKCoveySDKiefferTJ2011Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling. Diabetes6014141423. doi:10.2337/db10-0958.

    • Search Google Scholar
    • Export Citation
  • DubucPU1976The development of obesity, hyperinsulinemia, and hyperglycemia in ob/ob mice. Metabolism2515671574. doi:10.1016/0026-0495(76)90109-8.

    • Search Google Scholar
    • Export Citation
  • EmilssonVLiuYLCawthorneMAMortonNMDavenportM1997Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes46313316. doi:10.2337/diabetes.46.2.313.

    • Search Google Scholar
    • Export Citation
  • FehmannHCBodeHPEbertTKarlAGokeB1997aInteraction of GLP-I and leptin at rat pancreatic B-cells: effects on insulin secretion and signal transduction. Hormone and Metabolic Research29572576. doi:10.1055/s-2007-979103.

    • Search Google Scholar
    • Export Citation
  • FehmannHCPeiserCBodeHPStammMStaatsPHedetoftCLangREGokeB1997bLeptin: a potent inhibitor of insulin secretion. Peptides1812671273. doi:10.1016/S0196-9781(97)00135-6.

    • Search Google Scholar
    • Export Citation
  • FruhbeckG2006Intracellular signalling pathways activated by leptin. Biochemical Journal393720. doi:10.1042/BJ20051578.

  • FujikawaTChuangJCSakataIRamadoriGCoppariR2010Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. PNAS1071739117396. doi:10.1073/pnas.1008025107.

    • Search Google Scholar
    • Export Citation
  • GenuthSMPrzybylskiRJRosenbergDM1971Insulin resistance in genetically obese, hyperglycemic mice. Endocrinology8812301238. doi:10.1210/endo-88-5-1230.

    • Search Google Scholar
    • Export Citation
  • GermanJPThalerJPWisseBEOh-ISSarrufDAMatsenMEFischerJDTaborskyGJJrSchwartzMWMortonGJ2011Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology152394404. doi:10.1210/en.2010-0890.

    • Search Google Scholar
    • Export Citation
  • GraySLDonaldCJethaACoveySDKiefferTJ2010Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic β-cell leptin signaling. Endocrinology15141784186. doi:10.1210/en.2010-0102.

    • Search Google Scholar
    • Export Citation
  • HarveyJHardySCIrvingAJAshfordML2000Leptin activation of ATP-sensitive K+ (KATP) channels in rat CRI-G1 insulinoma cells involves disruption of the actin cytoskeleton. Journal of Physiology52795107. doi:10.1111/j.1469-7793.2000.00095.x.

    • Search Google Scholar
    • Export Citation
  • HekermanPZeidlerJKorfmacherSBamberg-LemperSKnobelspiesHZabeauLTavernierJBeckerW2007Leptin induces inflammation-related genes in RINm5F insulinoma cells. BMC Molecular Biology841doi:10.1186/1471-2199-8-41.

    • Search Google Scholar
    • Export Citation
  • HillJWEliasCFFukudaMWilliamsKWBerglundEDHollandWLChoYRChuangJCXuYChoiM2010Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metabolism11286297. doi:10.1016/j.cmet.2010.03.002.

    • Search Google Scholar
    • Export Citation
  • HuoLGamberKGreeleySSilvaJHuntoonNLengXHBjorbaekC2009Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metabolism9537547. doi:10.1016/j.cmet.2009.05.003.

    • Search Google Scholar
    • Export Citation
  • IslamMSMortonNMHanssonAEmilssonV1997Rat insulinoma-derived pancreatic β-cells express a functional leptin receptor that mediates a proliferative response. Biochemical and Biophysical Research Communications238851855. doi:10.1006/bbrc.1997.7399.

    • Search Google Scholar
    • Export Citation
  • IslamMSSjoholmAEmilssonV2000Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells. International Journal of Obesity and Related Metabolic Disorders2412461253. doi:10.1038/sj.ijo.0801370.

    • Search Google Scholar
    • Export Citation
  • KarlsenAERonnSGLindbergKJohannesenJGalsgaardEDPociotFNielsenJHMandrup-PoulsenTNerupJBillestrupN2001Suppressor of cytokine signaling 3 (SOCS-3) protects β-cells against interleukin-1β- and interferon-gamma-mediated toxicity. PNAS981219112196. doi:10.1073/pnas.211445998.

    • Search Google Scholar
    • Export Citation
  • KiefferTJHellerRSHabenerJF1996Leptin receptors expressed on pancreatic β-cells. Biochemical and Biophysical Research Communications224522527. doi:10.1006/bbrc.1996.1059.

    • Search Google Scholar
    • Export Citation
  • KiefferTJHellerRSLeechCAHolzGGHabenerJF1997Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic β-cells. Diabetes4610871093. doi:10.2337/diabetes.46.6.1087.

    • Search Google Scholar
    • Export Citation
  • KojimaSAsakawaAAmitaniHSakoguchiTUenoNInuiAKalraSP2009Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice. Peptides30962966. doi:10.1016/j.peptides.2009.01.007.

    • Search Google Scholar
    • Export Citation
  • KuehnenPLaubnerKRaileKSchoflCJakobFPilzIPathGSeufertJ2011Protein phosphatase 1 (PP-1)-dependent inhibition of insulin secretion by leptin in INS-1 pancreatic β-cells and human pancreatic islets. Endocrinology15218001808. doi:10.1210/en.2010-1094.

    • Search Google Scholar
    • Export Citation
  • KulkarniRNWangZLWangRMHurleyJDSmithDMGhateiMAWithersDJGardinerJVBaileyCJBloomSR1997Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice. Journal of Clinical Investigation10027292736. doi:10.1172/JCI119818.

    • Search Google Scholar
    • Export Citation
  • KushnerJAHajFGKlamanLDDowMAKahnBBNeelBGWhiteMF2004Islet-sparing effects of protein tyrosine phosphatase-1b deficiency delays onset of diabetes in IRS2 knockout mice. Diabetes536166. doi:10.2337/diabetes.53.1.61.

    • Search Google Scholar
    • Export Citation
  • LamNTCheungATRiedelMJLightPECheesemanCIKiefferTJ2004Leptin reduces glucose transport and cellular ATP levels in INS-1 β-cells. Journal of Molecular Endocrinology32415424. doi:10.1677/jme.0.0320415.

    • Search Google Scholar
    • Export Citation
  • LamNTCoveySDLewisJTOosmanSWebberTHsuECCheungATKiefferTJ2006Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver. Journal of Molecular Endocrinology36163174. doi:10.1677/jme.1.01937.

    • Search Google Scholar
    • Export Citation
  • LaubnerKKiefferTJLamNTNiuXJakobFSeufertJ2005Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic β-cells. Diabetes5434103417. doi:10.2337/diabetes.54.12.3410.

    • Search Google Scholar
    • Export Citation
  • Leclercq-MeyerVMalaisseWJ1998Failure of human and mouse leptin to affect insulin, glucagon and somatostatin secretion by the perfused rat pancreas at physiological glucose concentration. Molecular and Cellular Endocrinology141111118. doi:10.1016/S0303-7207(98)00087-2.

    • Search Google Scholar
    • Export Citation
  • LeeYHMagkosFMantzorosCSKangES2011Effects of leptin and adiponectin on pancreatic β-cell function. Metabolism6016641672. doi:10.1016/j.metabol.2011.04.008.

    • Search Google Scholar
    • Export Citation
  • LeviJGraySLSpeckMHuynhFKBabichSLGibsonWTKiefferTJ2011Acute disruption of leptin signaling in vivo leads to increased insulin levels and insulin resistance. Endocrinology15233853395. doi:10.1210/en.2011-0185.

    • Search Google Scholar
    • Export Citation
  • LicinioJMantzorosCNegraoABCizzaGWongMLBongiornoPBChrousosGPKarpBAllenCFlierJS1997Human leptin levels are pulsatile and inversely related to pituitary–adrenal function. Nature Medicine3575579. doi:10.1038/nm0597-575.

    • Search Google Scholar
    • Export Citation
  • LupiRMarchettiPMaffeiMDel GuerraSBenziLMarselliLBertaccaANavalesiR1999Effects of acute or prolonged exposure to human leptin on isolated human islet function. Biochemical and Biophysical Research Communications256637641. doi:10.1006/bbrc.1999.0384.

    • Search Google Scholar
    • Export Citation
  • MaedlerKSergeevPEhsesJAMatheZBoscoDBerneyTDayerJMReineckeMHalbanPADonathMY2004Leptin modulates β cell expression of IL-1 receptor antagonist and release of IL-1β in human islets. PNAS10181388143. doi:10.1073/pnas.0305683101.

    • Search Google Scholar
    • Export Citation
  • MaedlerKSchulthessFTBielmanCBerneyTBonnyCPrentkiMDonathMYRoduitR2008Glucose and leptin induce apoptosis in human β-cells and impair glucose-stimulated insulin secretion through activation of c-Jun N-terminal kinases. FASEB Journal2219051913. doi:10.1096/fj.07-101824.

    • Search Google Scholar
    • Export Citation
  • MantzorosCSMagkosFBrinkoetterMSienkiewiczEDardenoTAKimSYHamnvikOPKoniarisA2011Leptin in human physiology and pathophysiology. American Journal of Physiology. Endocrinology and Metabolism301E567E584. doi:10.1152/ajpendo.00315.2011.

    • Search Google Scholar
    • Export Citation
  • MeyerCRobsonDRackovskyNNadkarniVGerichJ1997Role of the kidney in human leptin metabolism. American Journal of Physiology273E903E907.

  • MoriokaTAsilmazEHuJDishingerJFKurpadAJEliasCFLiHElmquistJKKennedyRTKulkarniRN2007Disruption of leptin receptor expression in the pancreas directly affects β cell growth and function in mice. Journal of Clinical Investigation11728602868. doi:10.1172/JCI30910.

    • Search Google Scholar
    • Export Citation
  • MorrisDLRuiL2009Recent advances in understanding leptin signaling and leptin resistance. American Journal of Physiology. Endocrinology and Metabolism297E1247E1259. doi:10.1152/ajpendo.00274.2009.

    • Search Google Scholar
    • Export Citation
  • MortonGJSchwartzMW2011Leptin and the central nervous system control of glucose metabolism. Physiological Reviews91389411. doi:10.1152/physrev.00007.2010.

    • Search Google Scholar
    • Export Citation
  • MortonGJKaiyalaKJFisherJDOgimotoKSchwartzMWWisseBE2011Identification of a physiological role for leptin in the regulation of ambulatory activity and wheel running in mice. American Journal of Physiology. Endocrinology and Metabolism300E392E401. doi:10.1152/ajpendo.00546.2010.

    • Search Google Scholar
    • Export Citation
  • MyersMGJrLeibelRLSeeleyRJSchwartzMW2010Obesity and leptin resistance: distinguishing cause from effect. Trends in Endocrinology and Metabolism21643651. doi:10.1016/j.tem.2010.08.002.

    • Search Google Scholar
    • Export Citation
  • NaitoMFujikuraJEbiharaKMiyanagaFYokoiHKusakabeTYamamotoYSonCMukoyamaMHosodaK2011Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice. Diabetes6022652273. doi:10.2337/db10-1795.

    • Search Google Scholar
    • Export Citation
  • NaveHMuellerGSiegmundBJacobsRStrohTSchuelerUHopfeMBehrendtPBuchenauerTPabstR2008Resistance of Janus kinase-2 dependent leptin signaling in natural killer (NK) cells: a novel mechanism of NK cell dysfunction in diet-induced obesity. Endocrinology14933703378. doi:10.1210/en.2007-1516.

    • Search Google Scholar
    • Export Citation
  • NingKMillerLCLaidlawHABurgessLAPereraNMDownesCPLeslieNRAshfordML2006A novel leptin signalling pathway via PTEN inhibition in hypothalamic cell lines and pancreatic β-cells. EMBO Journal2523772387. doi:10.1038/sj.emboj.7601118.

    • Search Google Scholar
    • Export Citation
  • OkuyaSTanabeKTanizawaYOkaY2001Leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis. Endocrinology14248274830. doi:10.1210/en.142.11.4827.

    • Search Google Scholar
    • Export Citation
  • OzcanLErginASLuAChungJSarkarSNieDMyersMGJrOzcanU2009Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metabolism93551. doi:10.1016/j.cmet.2008.12.004.

    • Search Google Scholar
    • Export Citation
  • PallettALMortonNMCawthorneMAEmilssonV1997Leptin inhibits insulin secretion and reduces insulin mRNA levels in rat isolated pancreatic islets. Biochemical and Biophysical Research Communications238267270. doi:10.1006/bbrc.1997.7274.

    • Search Google Scholar
    • Export Citation
  • ParkSAhnISKimDS2010Central infusion of leptin improves insulin resistance and suppresses β-cell function, but not β-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model. Life Sciences86854862. doi:10.1016/j.lfs.2010.03.021.

    • Search Google Scholar
    • Export Citation
  • PelleymounterMACullenMJBakerMBHechtRWintersDBooneTCollinsF1995Effects of the obese gene product on body weight regulation in ob/ob mice. Science269540543. doi:10.1126/science.7624776.

    • Search Google Scholar
    • Export Citation
  • PerezCFernandez-GalazCFernandez-AgulloTArribasCAndresARosMCarrascosaJM2004Leptin impairs insulin signaling in rat adipocytes. Diabetes53347353. doi:10.2337/diabetes.53.2.347.

    • Search Google Scholar
    • Export Citation
  • PoitoutVRouaultCGuerre-MilloMBriaudIReachG1998Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans. Endocrinology139822826. doi:10.1210/en.139.3.822.

    • Search Google Scholar
    • Export Citation
  • PrpicVWatsonPMFramptonICSabolMAJezekGEGettysTW2003Differential mechanisms and development of leptin resistance in A/J versus C57BL/6J mice during diet-induced obesity. Endocrinology14411551163. doi:10.1210/en.2002-220835.

    • Search Google Scholar
    • Export Citation
  • SachdevaMMStoffersDA2009Minireview: meeting the demand for insulin: molecular mechanisms of adaptive postnatal β-cell mass expansion. Molecular Endocrinology23747758. doi:10.1210/me.2008-0400.

    • Search Google Scholar
    • Export Citation
  • SchwartzMWBaskinDGBukowskiTRKuijperJLFosterDLasserGPrunkardDEPorteDJrWoodsSCSeeleyRJ1996Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes45531535. doi:10.2337/diabetes.45.4.531.

    • Search Google Scholar
    • Export Citation
  • SeufertJ2004Leptin effects on pancreatic β-cell gene expression and function. Diabetes53 (Suppl 1) S152S158. doi:10.2337/diabetes.53.2007.S152.

    • Search Google Scholar
    • Export Citation
  • SeufertJKiefferTJHabenerJF1999aLeptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice. PNAS96674679. doi:10.1073/pnas.96.2.674.

    • Search Google Scholar
    • Export Citation
  • SeufertJKiefferTJLeechCAHolzGGMoritzWRicordiCHabenerJF1999bLeptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. Journal of Clinical Endocrinology and Metabolism84670676. doi:10.1210/jc.84.2.670.

    • Search Google Scholar
    • Export Citation
  • ShimabukuroMWangMYZhouYTNewgardCBUngerRH1998Protection against lipoapoptosis of β cells through leptin-dependent maintenance of Bcl-2 expression. PNAS9595589561. doi:10.1073/pnas.95.16.9558.

    • Search Google Scholar
    • Export Citation
  • ShimomuraIHammerREIkemotoSBrownMSGoldsteinJL1999Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature4017376. doi:10.1038/43448.

    • Search Google Scholar
    • Export Citation
  • SteinbergGRWattMJFamBCProiettoJAndrikopoulosSAllenAMFebbraioMAKempBE2006Ciliary neurotrophic factor suppresses hypothalamic AMP-kinase signaling in leptin-resistant obese mice. Endocrinology14739063914. doi:10.1210/en.2005-1587.

    • Search Google Scholar
    • Export Citation
  • TanabeKOkuyaSTanizawaYMatsutaniAOkaY1997Leptin induces proliferation of pancreatic β cell line MIN6 through activation of mitogen-activated protein kinase. Biochemical and Biophysical Research Communications241765768. doi:10.1006/bbrc.1997.7894.

    • Search Google Scholar
    • Export Citation
  • TanizawaYOkuyaSIshiharaHAsanoTYadaTOkaY1997Direct stimulation of basal insulin secretion by physiological concentrations of leptin in pancreatic β cells. Endocrinology13845134516. doi:10.1210/en.138.10.4513.

    • Search Google Scholar
    • Export Citation
  • TsiotraPCTsigosCRaptisSA2001TNFalpha and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells. International Journal of Obesity and Related Metabolic Disorders2510181026. doi:10.1038/sj.ijo.0801657.

    • Search Google Scholar
    • Export Citation
  • WangMYKoyamaKShimabukuroMMangelsdorfDNewgardCBUngerRH1998aOverexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion. PNAS951192111926. doi:10.1073/pnas.95.20.11921.

    • Search Google Scholar
    • Export Citation
  • WangMYKoyamaKShimabukuroMNewgardCBUngerRH1998bOB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype. PNAS95714718. doi:10.1073/pnas.95.2.714.

    • Search Google Scholar
    • Export Citation
  • WangMYChenLClarkGOLeeYStevensRDIlkayevaORWennerBRBainJRCharronMJNewgardCB2010Leptin therapy in insulin-deficient type I diabetes. PNAS10748134819. doi:10.1073/pnas.0909422107.

    • Search Google Scholar
    • Export Citation
  • YuXParkBHWangMYWangZVUngerRH2008Making insulin-deficient type 1 diabetic rodents thrive without insulin. PNAS1051407014075. doi:10.1073/pnas.0806993105.

    • Search Google Scholar
    • Export Citation
  • ZhangXZhangGZhangHKarinMBaiHCaiD2008Hypothalamic IKKβ/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell1356173. doi:10.1016/j.cell.2008.07.043.

    • Search Google Scholar
    • Export Citation
  • ZhaoAZBornfeldtKEBeavoJA1998Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. Journal of Clinical Investigation102869873. doi:10.1172/JCI3920.

    • Search Google Scholar
    • Export Citation