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|عنوان فارسی مقاله:||۲۰ سال لپتین: ارتباط سیگنال دهی لپتین با عملکرد بیولوژیکی|
|عنوان انگلیسی مقاله:||۲۰ years of leptin: connecting leptin signaling to biological function|
|رشته های مرتبط:||زیست شناسی، علوم سلولی و مولکولی، میکروبیولوژی و بیوانفورماتیک|
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Hypothalamic leptin action promotes negative energy balance and modulates glucose homeostasis, as well as serving as a permissive signal to the neuroendocrine axes that control growth and reproduction. Since the initial discovery of leptin 20 years ago, we have learned a great deal about the molecular mechanisms of leptin action. An important aspect of this has been the dissection of the cellular mechanisms of leptin signaling, and how specific leptin signals influence physiology. Leptin acts via the long form of the leptin receptor LepRb. LepRb activation and subsequent tyrosine phosphorylation recruits and activates multiple signaling pathways, including STAT transcription factors, SHP2 and ERK signaling, the IRS-protein/ PI3Kinase pathway, and SH2B1. Each of these pathways controls specific aspects of leptin action and physiology. Important inhibitory pathways mediated by suppressor of cytokine signaling proteins and protein tyrosine phosphatases also limit physiologic leptin action. This review summarizes the signaling pathways engaged by LepRb and their effects on energy balance, glucose homeostasis, and reproduction. Particular emphasis is given to the multiple mouse models that have been used to elucidate these functions in vivo.
Obesity and its many comorbidities present a significant challenge to public health in the USA. The health care costs associated with obesity totaled more than $147 billion annually. In addition to the economic burden, obesity results in premature death and disability from stroke, cardiovascular disease, and type 2 diabetes mellitus (http://www.cdc.gov/obesity/data/adult.html accessed 6/29/14). Furthermore, the obesity epidemic is no longer confined to the USA. Worldwide, more than 1.4 billion adults were overweight or obese in 2008 (Danaei et al. 2011). Clearly, the need for anti-obesity therapies is large and growing larger, yet no pharmacotherapies have been achieved more than minimal success in promoting long-term weight loss. At its most basic level, body weight is determined by the amount of energy taken in relative to energy expenditure (Schwartz et al. 2000). If energy intake exceeds energy expenditure, excess energy accumulates in the form of triglycerides stored in adipose tissue, resulting in weight gain and obesity. However, the brain integrates signals of long-term energy stores with other physiologic inputs to modulate energy intake relative to energy expenditure. When adipose energy (fat) stores fall, hunger increases and energy expenditure decreases to defend body energy stores; conversely, the brain responds to nutritional surfeit by permitting increased energy expenditure and decreased feeding to maintain a constant body weight. One of the most important and widely studied players in the control of energy balance is the hormone leptin (Friedman & Halaas 1998, Elmquist et al. 2005). Leptin was discovered by Zhang et al. (1994). Defects in leptin production underlie the massive obesity observed in ob/ob mice. Leptin is produced in adipose tissue in proportion to triglyceride stores, and serves as a critical indicator of an organism’s long-term energy status (Frederich et al. 1995a, Maffei et al. 1995). Leptin acts primarily in the brain, especially the hypothalamus, where its action is integrated with that of other adipokines, gastrokines, and other signals to coordinate energy homeostasis (Friedman & Halaas 1998, Bates & Myers 2003, Myers et al. 2009, Ring & Zeltser 2010). In addition to leptin-deficient ob/ob mice, rare human mutations resulting in leptin deficiency have also been identified; leptin-deficient mice and humans display hyperphagia, decreased energy expenditure, and early-onset obesity (Montague et al. 1997, Farooqi et al. 1999). Leptin receptor (LepRb)-deficient humans and db/db mice display a similar phenotype (Tartaglia et al. 1995, Chua et al. 1996). Numerous studies have elaborated the critical role of leptin in the modulation of energy balance: the lack of leptin, as in starvation or genetic leptin deficiency, increases hunger while promoting an energysparing program of neuroendocrine and autonomic changes, including decreased sympathetic nervous system tone, thyroid function, growth, and reproduction (Ahima et al. 1997). Leptin treatment largely reverses these changes (Farooqi et al. 1999, 2002). Decreased leptin also promotes a variety of other behavioral and physiologic changes to respond appropriately to low energy stores (Lu et al. 2006, Liu et al. 2010, 2011). Despite the initial heralding of leptin as a potential cure for human obesity, most obese humans exhibit high circulating leptin concentrations (Maffei et al. 1995). Serum leptin increases in proportion to body fat percentage; obese patients secrete leptin at levels appropriate for their increased adipose mass and display elevated leptin concentrations (‘hyperleptinemia’) relative to lean controls (Tobe et al. 1999). Clearly, however, these high circulating leptin levels do not suffice to restore body adiposity to lean levels, as might be predicted based on the sensitivity of organisms to decreases in leptin signaling. Whether this inability of leptin to suppress feeding in the face of obesity results from an intrinsic or acquired defect in leptin action, or rather simply reflects the inability of homeostatic controls to overcome hedonic feeding drives remains a matter of debate. This controversy serves to underscore the importance of developing a more complete understanding of leptin signaling, its cellular effects, target neural pathways, and integration with other determinants of energy homeostasis (Figs 1 and 2).
Leptin and the LepRb
Leptin is a 146 amino acid protein produced in white adipose tissue in proportion to triglyceride stores (Frederich et al. 1995b). Once secreted into the circulation, leptin travels to the brain, where it enters the CNS, presumably via the choroid plexus and circumventricular organs. In the brain, leptin acts by binding and activating the long form of LepRb, which is expressed primarily on specialized subsets of neurons in certain hypothalamic and brainstem nuclei (Tartaglia 1997, Elias et al. 2000, Scott et al. 2009, Patterson et al. 2011). Mutations that inactivate LepRb, as well as antagonists of LepRb activation, confirm that leptin binding to LepRb is required for its biological activity (Chen et al. 1996, Shpilman et al. 2011). While the LEPR gene encodes multiple isoforms (LepRa-f in rats), only LepRb contains the full intracellular domain necessary for the activation of critical second messenger pathways and normal leptin action (Chua et al. 1996, 1997, Lee et al. 1996, Tartaglia 1997). Many functions for the other (‘short’) forms of the receptor have been hypothesized, including actions as a serumbinding protein that functions in leptin stabilization or sequestration (Zastrow et al. 2003, Yang et al. 2004, Zhang & Scarpace 2009), or as a leptin transporter (Bjorbaek et al. 1998a, Kastin et al. 1999), but LepRb alone suffices for the control of energy balance, glucose homeostasis, and other leptin effects, and LepRb thus constitutes the focus of this review.