Ghrelin, the endogenous ligand of the GH secretagogue receptor, has a pleiotropic role in the modulation of energy balance. Recent evidence has demonstrated that besides its orexigenic role, ghrelin regulates central and peripheral lipid metabolism through specific control of hypothalamic AMP-activated protein kinase (AMPK), a critical metabolic gauge regulating both cellular and whole-body energy homeostasis. In this review, we summarize the new milestones of ghrelin's actions on energy balance, with particular focus on its molecular interaction with hypothalamic AMPK and fatty acid metabolism. Understanding this new metabolic pathway can provide new therapeutic targets for the treatment of obesity and the metabolic syndrome.
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- Abstract: Thyroid* x
- Abstract: Digestion x
- Abstract: Thyroxine x
- Abstract: Thyroglobulin x
- Abstract: Thyroiditis x
- Abstract: Thyrotoxicosis x
- Abstract: Hypothyroidism x
- Abstract: Hyperthyroidism x
- Abstract: TSHR x
- Abstract: Metabolism x
Luis Varela, María J Vázquez, Fernando Cordido, Rubén Nogueiras, Antonio Vidal-Puig, Carlos Diéguez and Miguel López
Emily Tubbs and Jennifer Rieusset
Beyond the maintenance of cellular homeostasis and the determination of cell fate, ER–mitochondria contact sites, defined as mitochondria-associated membranes (MAM), start to emerge as an important signaling hub that integrates nutrient and hormonal stimuli and adapts cellular metabolism. Here, we summarize the established structural and functional features of MAM and mainly focus on the latest breakthroughs highlighting a crucial role of organelle crosstalk in the control of metabolic homeostasis. Lastly, we discuss recent studies that have revealed the importance of MAM in not only metabolic diseases but also in other pathologies with disrupted metabolism, shedding light on potential common molecular mechanisms and leading hopefully to novel treatment strategies.
G W Montgomery, M L Tate, H M Henry, J M Penty and R M Rohan
Restriction fragment length polymorphisms were identified in sheep and deer using ovine cDNA probes for the FSH receptor (FSHR) and the LH receptor (LHCGR). FSHR and LHCGR were closely linked in sheep with no recombinants and neither receptor was linked to the Booroola fecundity gene (FecB). Both receptors were also closely linked in deer at a map distance of 3·3 cM. Linkage between the receptor genes assigns FSHR to sheep chromosome 3. Sequence analysis showed that the mammalian LHCGRs and FSHRs are more similar to each other than to mammalian TSH receptor (TSHR). Taken together, these data suggest that TSHR and the LHCGR/FSHR arose from a common ancestral gene by a process of chromosomal duplication. Subsequent duplication of the region containing the LH/FSH receptor and functional divergence could have given rise to the two gonadotrophin receptors present in mammals today.
Marina R Pulido, Yoana Rabanal-Ruiz, Farid Almabouada, Alberto Díaz-Ruiz, María A Burrell, María J Vázquez, Justo P Castaño, Rhonda D Kineman, Raúl M Luque, Carlos Diéguez, Rafael Vázquez-Martínez and María M Malagón
There is increasing evidence that proteins associated with lipid droplets (LDs) play a key role in the coordination of lipid storage and mobilization in adipocytes. The small GTPase, RAB18, has been recently identified as a novel component of the protein coat of LDs and proposed to play a role in both β-adrenergic stimulation of lipolysis and insulin-induced lipogenesis in 3T3-L1 adipocytes. In order to better understand the role of Rab18 in the regulation of lipid metabolism in adipocytes, we evaluated the effects of age, fat location, metabolic status, and hormonal milieu on Rab18 expression in rodent white adipose tissue (WAT). Rab18 mRNA was undetectable at postnatal day 15 (P15), but reached adult levels by P45, in both male and female rats. In adult rats, Rab18 immunolocalized around LDs, as well as within the cytoplasm of mature adipocytes. A weak Rab18 signal was also detected in the stromal-vascular fraction of WAT. In mice, fasting significantly increased, though with a distinct time–course pattern, Rab18 mRNA and protein levels in visceral and subcutaneous WAT. The expression of Rab18 was also increased in visceral and subcutaneous WAT of obese mice (diet-induced, ob/ob, and New Zealand obese mice) compared with lean controls. Rab18 expression in rats was unaltered by castration, adrenalectomy, or GH deficiency but was increased by hypophysectomy, as well as hypothyroidism. When viewed together, our results suggest the participation of Rab18 in the regulation of lipid processing in adipose tissue under both normal and pathological conditions.
Kristine M Wadosky, Jessica M Berthiaume, Wei Tang, Makhosi Zungu, Michael A Portman, A Martin Gerdes and Monte S Willis
Thyroid hormone (TH) is recognized for its role in cellular metabolism and growth and participates in homeostasis of the heart. T3 activates pro-survival pathways including Akt and mTOR. Treatment with T3 after myocardial infarction is cardioprotective and promotes elements of physiological hypertrophic response after cardiac injury. Although T3 is known to benefit the heart, very little about its regulation at the molecular level has been described to date. The ubiquitin proteasome system (UPS) regulates nuclear hormone receptors such as estrogen, progesterone, androgen, and glucocorticoid receptors by both degradatory and non-degradatory mechanisms. However, how the UPS regulates T3-mediated activity is not well understood. In this study, we aim to determine the role of the muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) in regulating T3-induced cardiomyocyte growth. An increase in MuRF1 expression inhibits T3-induced physiological cardiac hypertrophy, whereas a decrease in MuRF1 expression enhances T3's activity both in vitro and in cardiomyocytes in vivo. MuRF1 interacts directly with TRα to inhibit its activity by posttranslational ubiquitination in a non-canonical manner. We then demonstrated that a nuclear localization apparatus that regulates/inhibits nuclear receptors by sequestering them within a subcompartment of the nucleus was necessary for MuRF1 to inhibit T3 activity. This work implicates a novel mechanism that enhances the beneficial T3 activity specifically within the heart, thereby offering a potential target to enhance cardiac T3 activity in an organ-specific manner.
Xilin Yang, Zezhang Tao, Zhanyong Zhu, Hua Liao, Yueqiang Zhao and Huajun Fan
Insulin plays an important role in the regulation of glucose metabolism. However, the molecular mechanisms involved are not entirely clarified. In this context, we found that miR-593-3p negatively regulates insulin-regulated glucose metabolism in hepatocellular carcinoma HepG2 and Bel7402 cells. We then identified Slc38a1 and CLIP3 as novel targets of miR-593-3p. Further studies demonstrated that Slc38a1 and CLIP3 mediate insulin-regulated glucose metabolism. Interestingly, we also demonstrated that miR-593-3p expression was negatively associated with Slc38a1 and CLIP3 expression in insulin-treated HepG2 cells, and insulin-induced Slc38a1 and CLIP3 expression via downregulation of miR-593-3p. Taken together, this study indicates that inhibition of miRNA-593-3p by insulin promotes glucose metabolism through the regulation of Slc38a1 and CLIP3 expression, and provides a new insight into the role and mechanism of insulin-induced glycolysis.
Suzy S J Hur, Jennifer E Cropley and Catherine M Suter
Parental health or exposures can affect the lifetime health outcomes of offspring, independently of inherited genotypes. Such ‘epigenetic’ effects occur over a broad range of environmental stressors, including defects in parental metabolism. Although maternal metabolic effects are well documented, it has only recently been established that that there is also an independent paternal contribution to long-term metabolic health. Both paternal undernutrition and overnutrition can induce metabolic phenotypes in immediate offspring, and in some cases, the induced phenotype can affect multiple generations, implying inheritance of an acquired trait. The male lineage transmission of metabolic disease risk in these cases implicates a heritable factor carried by sperm. Sperm-based transmission provides a tractable system to interrogate heritable epigenetic factors influencing metabolism, and as detailed here, animal models of paternal programming have already provided some significant insights. Here, we review the evidence for paternal programming of metabolism in humans and animal models, and the available evidence on potential underlying mechanisms. Programming by paternal metabolism can be observed in multiple species across animal phyla, suggesting that this phenomenon may have a unique evolutionary significance.
Nora Martínez, Melisa Kurtz, Evangelina Capobianco, Romina Higa, Verónica White and Alicia Jawerbaum
Maternal diabetes impairs fetoplacental metabolism and growth. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor capable of regulating lipid metabolism and inflammatory pathways. In this study, we analyzed whether placental and fetal PPARα activation regulates lipid metabolism and nitric oxide (NO) production in term placentas from diabetic rats. Diabetes was induced by neonatal streptozotocin administration. On day 21 of pregnancy, placentas from control and diabetic rats were cultured in the presence of PPARα agonists (clofibrate and leukotriene B4 (LTB4)) for further evaluation of levels, synthesis, and peroxidation of lipids as well as NO production. Besides, on days 19, 20, and 21 of gestation, fetuses were injected with LTB4, and the placentas were explanted on day 21 of gestation for evaluation of placental weight and concentrations of placental lipids, lipoperoxides, and NO metabolites. We found that placentas from diabetic rats showed reduced PPARα concentrations. They presented no lipid overaccumulation but reduced lipid synthesis, parameters negatively regulated by PPARα activators. Lipid peroxidation and NO production, increased in placentas from diabetic rats, were negatively regulated by PPARα activators. Fetal PPARα activation in diabetic rats does not change placental lipid concentrations but reduced placental weight and NO production. In conclusion, PPARα activators regulate lipid metabolism and NO production in term placentas from diabetic rats, an activation that regulates placental growth and can partly be exerted by the developing fetus.
Obesity and secondary development of type 2 diabetes (T2D) are major health care problems throughout the developed world. Accumulating evidence suggest that glycerol metabolism contributes to the pathophysiology of obesity and T2D. Glycerol is a small molecule that serves as an important intermediate between carbohydrate and lipid metabolism. It is stored primarily in adipose tissue as the backbone of triglyceride (TG) and during states of metabolic stress, such as fasting and diabetes, it is released for metabolism in other tissues. In the liver, glycerol serves as a gluconeogenic precursor and it is used for the esterification of free fatty acid into TGs. Aquaporin 7 (AQP7) in adipose tissue and AQP9 in the liver are transmembrane proteins that belong to the subset of AQPs called aquaglyceroporins. AQP7 facilitates the efflux of glycerol from adipose tissue and AQP7 deficiency has been linked to TG accumulation in adipose tissue and adult onset obesity. On the other hand, AQP9 expressed in liver facilitates the hepatic uptake of glycerol and thereby the availability of glycerol for de novo synthesis of glucose and TG that both are involved in the pathophysiology of diabetes. The aim of this review was to summarize the current knowledge on the role of the two glycerol channels in controlling glycerol metabolism in adipose tissue and liver.
Evan R Simpson and Kristy A Brown
Obesity is now recognised to be an inflammatory condition in which dysregulated metabolism plays an integral role. Inflammatory mediators regulate aromatase expression in the human breast as one mechanism whereby they increase the risk of breast cancer, especially in women who are obese.