Sixteen years and counting: an update on leptin in energy balance

Abstract

Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles. IntroductionThe nervous system regulates energy balance at the organismal level by constantly adjusting energy intake, expenditure, and storage. The influence of the nervous system over metabolic functions was first suggested at the beginning of the 20th century when excessive adiposity was associated with pituitary tumors and injury to the hypothalamus (1). However, it was not until the 1940s that selective surgical lesions of certain hypothalamic areas were found to result in extreme obesity or leanness in rats (2, 3). Over the last few decades, numerous discoveries substantially extended our understanding of the neural control of metabolism. However, it is safe to say that none were more important than the cloning of the ob gene by Friedman and colleagues in 1994 (4). The ob gene encodes the protein leptin, which is a hormone produced and secreted by the white adipose tissue, and consequently, its circulating levels are closely related to body fat mass (5, 6). Leptin deficiency in mice homozygous for a mutant ob gene (ob/ob mice) causes morbid obesity, diabetes, and various neuroendocrine anomalies, and leptin replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure (7-10). Several splice variants of the leptin receptor have been identified, and the "short forms" are widely expressed in multiple tissues (11). The "long form" of the leptin receptor encodes a protein with a longer cytoplasmic domain (OB-Rb) that is highly expressed in particular sites within the CNS (refs. 10, 12, and Table 1). The short forms of the leptin receptor are also present within the CNS (11), but OB-Rb is sufficient for leptin actions on metabolism (13,14). OB-Rb is a type 1 cytokine receptor, which stimulates the JAK/STAT3 pathway (15) and PI3K (16,17). Leptin induces transcriptional changes of several genes via the JAK/STAT3 pathway, and rapid changes in cellular activity and membrane potential may underlie the acute actions of leptin (18). While actions of this hormone in peripheral tissues have been identified, studies in genetically modified mice have demonstrated that leptin action only in the CNS is sufficient to regulate body weight, feeding, energy expenditure, and glucose metabolism (13,(19)(20)(21).Since leptin is clearly not the only metabolic signal acting on the brain, the range of its effects on behavior, metabolism, and endocrinology is trul...

Interactions between endocrine and circadian systems

“…Circulating leptin shows a diurnal rhythm, peaking in the night in humans. In the models of obesity, leptin resistance can occur and in the absence of leptin's anorexigenic effects, this is accompanied by overeating (reviewed in Gautron & Elmquist (2011)). In humans, acute HFD feeding results in lower 24-h leptin (Havel et al 1999), whereas hyperleptinemia and changes in leptin rhythmicity are observed in obese subjects in accordance with increased fat mass (Considine et al 1996, Rosenbaum et al 1996, van Dielen et al 2002.…”

Role of sex hormones in modulation of brown adipose tissue activity

“…Indeed, estrogen action in the hypothalamus increases the local action of leptin (Brown et al 2010), whose catabolic effects in the brain are known to inhibit food intake and increase energy expenditure (Gautron & Elmquist 2011). Moreover, estrogen may regulate energy balance by enhancing leptin-induced activation of the SNS, which innervates the WAT, thereby reducing fat mass through stimulation of SNS-dependent lipolysis (Haifei et al 2009).…”

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition

“…Leptin provides the most robust adipostatic signals, whereas insulin, cholecystokinin, ghrelin, glucagonlike peptide-1 (GLP1), and a number of nutrients act as modulators of the activity of such neurons (4,5,6,7).…”