20 years of leptin: connecting leptin signaling to biological function.

Obesity and its many comorbidities present a significant challenge to public health in the United States. The health care costs associated with obesity total 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 (T2DM) (http://www.cdc.gov/obesity/data/adult.html accessed 6/29/14). Furthermore, the obesity epidemic is no longer confined to the United States. 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 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. The brain integrates signals of long-term energy stores with other physiologic inputs to modulate energy intake relative to energy expenditure, however. 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 (Elmquist, et al. 2005; Friedman and Halaas 1998). Leptin was discovered by Friedman and colleagues in 1994; defects in leptin production underlie the massive obesity observed in ob/ob mice(Zhang, et al. 1994). 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 (Bates and Myers 2003; Friedman and Halaas 1998; Myers, et al. 2009; Ring and 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(Farooqi, et al. 1999; Montague, et al. 1997). Leptin receptor deficient humans and db/db mice display a similar phenotype (Chua, et al. 1996; Tartaglia, et al. 1995). Numerous studies have elaborated the critical role for leptin in the modulation of energy balance: the lack of leptin, as in starvation or genetic leptin deficiency, increases hunger while promoting an energy-sparing 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; Farooqi, et al. 2002). Decreased leptin also promotes a variety of other behavioral and physiologic changes to respond appropriately to low energy stores(Liu, et al. 2010; Liu, et al. 2011; Lu, et al. 2006). 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.