The pituitary gland regulates diverse physiological functions, including growth, metabolism, reproduction, stress response, and ageing. Early genetic models in the mouse taught us that the pituitary is highly sensitive to genetic alteration of specific cell cycle regulators such as the retinoblastoma protein (pRB) or the cell cycle inhibitor p27Kip1. The molecular analysis of human pituitary neoplasias has now corroborated that cell cycle deregulation is significantly implicated in pituitary tumorigenesis. In particular, proteins involved in cyclin-dependent kinase regulation or the pRB pathway are altered in nearly all human pituitary tumors. Additional cell cycle regulators such as PTTG1/securin may have critical roles in promoting genomic instability in pituitary neoplasias. Recent experimental data suggest that these cell cycle regulators may have significant implications in the biology of putative progenitor cells and pituitary homeostasis. Understanding how cell cycle regulation controls pituitary biology may provide us with new therapeutic approaches against pituitary diseases.
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Victor Quereda and Marcos Malumbres
Keir Menzies and Johan Auwerx
In recent years, the role of acetylation has gained ground as an essential modulator of intermediary metabolism in skeletal muscle. Imbalance in energy homeostasis or chronic cellular stress, due to diet, aging, or disease, translate into alterations in the acetylation levels of key proteins which govern bioenergetics, cellular substrate use, and/or changes in mitochondrial content and function. For example, cellular stress induced by exercise or caloric restriction can alter the coordinated activity of acetyltransferases and deacetylases to increase mitochondrial biogenesis and function in order to adapt to low energetic levels. The natural duality of these enzymes, as metabolic sensors and effector proteins, has helped biologists to understand how the body can integrate seemingly distinct signaling pathways to control mitochondrial biogenesis, insulin sensitivity, glucose transport, reactive oxygen species handling, angiogenesis, and muscle satellite cell proliferation/differentiation. Our review will summarize the recent developments related to acetylation-dependent responses following metabolic stress in skeletal muscle.
T Miki, K Nagashima and S Seino
ATP-sensitive K+ channels (KATP channels) play important roles in many cellular functions by coupling cell metabolism to electrical activity. The KATP channels in pancreatic beta-cells are thought to be critical in the regulation of glucose-induced and sulfonylurea-induced insulin secretion. Until recently, however, the molecular structure of the KATP channel was not known. Cloning members of the novel inwardly rectifying K+ channel subfamily Kir6.0 (Kir6.1 and Kir6.2) and the sulfonylurea receptors (SUR1 and SUR2) has clarified the molecular structure of KATP channels. The pancreatic beta-cell KATP channel comprises two subunits: a Kir6.2 subunit and an SUR1 subunit. Molecular biological and molecular genetic studies have provided insights into the physiological and pathophysiological roles of the pancreatic beta-cell KATP channel in insulin secretion.
Michael Welsh, Maria Jamalpour, Guangxiang Zang and Björn Åkerblom
This review will describe the SH2-domain signaling protein Src Homology-2 domain containing protein B (SHB) and its role in various physiological processes relating in particular to glucose homeostasis and β cell function. SHB operates downstream of several tyrosine kinase receptors and assembles signaling complexes in response to receptor activation by interacting with other signaling proteins via its other domains (proline-rich, phosphotyrosine-binding and tyrosine-phosphorylation sites). The subsequent responses are context-dependent. Absence of Shb in mice has been found to exert effects on hematopoiesis, angiogenesis and glucose metabolism. Specifically, first-phase insulin secretion in response to glucose was impaired and this effect was related to altered characteristics of focal adhesion kinase activation modulating signaling through Akt, ERK, β catenin and cAMP. It is believed that SHB plays a role in integrating adaptive responses to various stimuli by simultaneously modulating cellular responses in different cell-types, thus playing a role in maintaining physiological homeostasis.
Eva Tudurí, Monica Imbernon, Rene Javier Hernández-Bautista, Marta Tojo, Johan Fernø, Carlos Diéguez and Rubén Nogueiras
GPR55 is a G-protein-coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological actions. Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of GPR55. In this review, we will focus on the role of GPR55 in energy balance and glucose metabolism. We will summarize its actions on feeding, nutrient partitioning, gastrointestinal motility and insulin secretion in preclinical models and the scarce data available in humans. The potential of GPR55 to become a new pharmaceutical target to treat obesity and type 2 diabetes, as well as the foreseeing difficulties are also discussed.
Obesity rates are increasing alongside those of its co-morbidities, placing a huge strain on health systems across the globe. Evidence points to inappropriate levels of ectopic lipid accumulation outside of adipose tissue being a major factor in the progression of many of these diseases. Brown adipose tissue (BAT) has a huge capacity to remove lipids from the circulatory system to fuel thermogenesis. Multiple studies have now confirmed the existence of active BAT in adult humans, making strategies aimed at activating it a potential therapeutic option in obese subjects. In recent years, researchers working in murine models have found a wide range of endogenous molecules with specific roles regulating BAT. These findings place BAT firmly within the wider network of physiological regulation covering global metabolism. They also highlight the possibility of targeting thermogenesis in a safe and specific manner to remove potentially harmful lipids released from stressed or failing white adipose tissue in obese states.
Viral Chikani and Ken K Y Ho
Skeletal muscle is a target tissue of GH. Based on its anabolic properties, it is widely accepted that GH enhances muscle performance in sports and muscle function in the elderly. This paper critically reviews information on the effects of GH on muscle function covering structure, protein metabolism, the role of IGF1 mediation, bioenergetics and performance drawn from molecular, cellular and physiological studies on animals and humans. GH increases muscle strength by enhancing muscle mass without affecting contractile force or fibre composition type. GH stimulates whole-body protein accretion with protein synthesis occurring in muscular and extra-muscular sites. The energy required to power muscle function is derived from a continuum of anaerobic and aerobic sources. Molecular and functional studies provide evidence that GH stimulates the anaerobic and suppresses the aerobic energy system, in turn affecting power-based functional measures in a time-dependent manner. GH exerts complex multi-system effects on skeletal muscle function in part mediated by the IGF system.
Lan Xu, Wenting Wang, Xinyue Zhang, Hanni Ke, Yingying Qin, Li You, Weiping Li, Gang Lu, Wai-Yee Chan, Peter C K Leung, Shidou Zhao and Zi-Jiang Chen
Obesity is a worldwide health problem with rising incidence and results in reproductive difficulties. Elevated saturated free fatty acids (FFAs) in obesity can cause insulin resistance (IR) in peripheral tissues. The high intra-follicular saturated FFAs may also account for IR in ovarian granulosa cells (GCs). In the present study, we investigated the relationship between saturated FFAs and IR in GCs by the use of palmitic acid (PA). We demonstrated that the glucose uptake in cultured GCs and lactate accumulation in the culture medium were stimulated by insulin, but the effects of insulin were attenuated by PA treatment. Besides, insulin-induced phosphorylation of Akt was reduced by PA in a dose- and time-dependent manner. Furthermore, PA increased phosphorylation of JNK and JNK blockage rescued the phosphorylation of Akt which was downregulated by PA. These findings highlighted the negative effect of PA on GCs metabolism and may partially account for the obesity-related reproductive disorders.
The signalling pathways utilised by insulin receptor (IR) and IGF receptor to transduce their diverse effects on cellular metabolism, growth and survival are well established in broad outline, but many details remain to be elucidated. Tyrosine phosphorylation of IR substrates and Shc initiates signalling via canonical phosphoinositide 3-kinase/Akt and Ras/MAP kinase pathways, which together mediate many of the actions of insulin and IGFs. However, a variety of additional substrates and scaffolds have been described that may play roles in modulating the canonical pathways or in specific biological responses. This review will focus on recent studies that have extended our understanding of insulin/IGF signalling pathways, and the elements that may contribute to specificity.
Amanda M Ackermann and Maureen Gannon
Pancreatic β-cells are responsible for producing all of the insulin required by an organism to maintain glucose homeostasis. Defects in development, maintenance, or expansion of β-cell mass can result in impaired glucose metabolism and diabetes. Thus, identifying the molecular regulators of these processes may provide new therapeutic targets for diabetes. Additionally, understanding the processes of β-cell differentiation and proliferation may allow for in vitro cultivation of β-cells in sufficient amounts to be transplanted into patients with diabetes. This review addresses many of the transcription factors and signaling pathways that play a role in early pancreatic development and endocrine cell (specifically β-cell) differentiation, conditions that influence β-cell mass development and molecular regulators of β-cell proliferation and apoptosis that are responsible for maintaining and expanding β-cell mass.