Leptin in the 21st CenturyPhysiology of leptin: energy homeostasis, neuroendocrine function and metabolism
Introduction
The discovery of leptin changed the knowledge of energy homeostasis and our view of adipose tissue from a simple energy depot to an active endocrine organ [1]. Leptin is mainly produced in adipose tissue and circulating leptin levels correlate well with the amount of body fat, reflecting energy status. Leptin plays an important role in regulating energy homeostasis, neuroendocrine and immune functions, and glucose, lipid and bone metabolism [2], [3]. While leptin administration reverses neuroendocrine and metabolic abnormalities in individuals with congenital leptin deficiency, common forms of obesity are typically associated with elevated leptin and resistance to leptin's effects on energy homeostasis [4]. Here, we review the biology of leptin, the current understanding of its physiologic and pathologic roles, and potential clinical applications.
Section snippets
Biology of leptin
Leptin is a 167-amino-acid peptide that is mainly expressed in white adipose tissue (WAT), but is also found in a variety of tissues including placenta, mammary gland, ovary, skeletal muscle, stomach, pituitary gland, and lymphoid tissue [5]. Circulating leptin levels are directly in proportion to the amount of body fat, thereby reflecting the status of long-term energy stores. In addition, leptin levels fluctuate according to changes in calorie intake with a marked decrease during starvation
Leptin and energy homeostasis
Leptin acts on LepRb-expressing neurons in the brain. In the arcuate nucleus (ARC), leptin interacts with a complex neural circuit to control food intake, activating anorexigenic neurons that synthesize pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), and inhibiting orexigenic neurons that synthesize agouti-related peptide (AgRP) and neuropeptide Y (NPY). During fasting, circulating leptin levels decline rapidly. The fall in leptin stimulates the expression
Leptin and neuroendocrine function
Leptin levels in adipose tissue and plasma fall rapidly during fasting. Circulating leptin levels decrease in overweight men after negative energy balance is achieved with exercise and calorie restriction, indicating that leptin levels reflect energy status [59]. Low leptin levels during fasting trigger metabolic and hormonal responses in mice and humans [11], [60], consisting of hyperphagia, hypogonadotropic hypogonadism, and suppression of thyroid and growth hormone (GH) levels, which are
Leptin and metabolism
Total leptin deficiency in ob/ob mice and individuals with congenital leptin deficiency results in insulin resistance, diabetes, steatosis and other features of metabolic syndrome. In ob/ob mice, leptin treatment rapidly decreases glucose, insulin and lipids before weight loss is achieved [53], [90] (Fig. 2). In morbidly obese individuals with congenital leptin deficiency, leptin replacement dramatically decreases insulin resistance, steatosis, dyslipidemia and glucose levels [54], [65].
Leptin and exercise
Successful long-term weight loss requires a reduction in food intake and an increase in physical activity. A negative energy balance achieved in 4 days by combining calorie restriction and exercise in obese subjects resulted in a rapid decline in leptin, indicating that changes in leptin levels reflect energy balance [59]. Human skeletal muscle expresses low levels of LepRb. As with plasma leptin levels, there is a sexual dimorphism in LepRb expression in human skeletal muscle, which could be
Leptin and immune function
Various studies have shown that leptin has important roles in modulating innate and adaptive immunity [144]. Leptin stimulates neutrophil chemotaxis and promotes macrophage phagocytosis, as well as production of pro-inflammatory cytokines such as interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α [145], [146]. Recently, it has also been shown that leptin acts as a negative signal for the proliferation of regulatory T cells, while stimulating T helper 1 cells [144], [147]. Thus, leptin may
Clinical applications of leptin
As mentioned earlier, leptin treatment has robust effects in states of leptin deficiency [154] (Fig. 1). Leptin replacement dramatically reduces body weight and fat, and reverses neuroendocrine and metabolic abnormalities in individuals with congenital leptin deficiency [54], [65]. Leptin administration in women with hypothalamic amenorrhea restores normal menstrual cycles, corrects abnormalities in the gonadal, thyroid and adrenal axes, and improves bone mineral density and markers of bone
Concluding remarks
Leptin is an adipocyte-secreted hormone that regulates food intake, energy homeostasis, neuroendocrine function, metabolism, and immune function. Studies have shown that leptin acts mainly on neuronal targets in the brain. Leptin replacement is an effective therapy in severe leptin deficiency, such as congenital leptin deficiency or generalized lipodystrophy. Further studies are needed to better understand the mechanisms underlying leptin resistance in common forms of obesity, and how these
Author contributions
H.K.P and R.S.A co-wrote the review article.
Conflict of interest
There are no potential conflicts of interest relevant to this article.
Acknowledgments
R.S.A is supported by National Institutes of Health grants P01-DK049210 and P30-DK19525.
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