Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice

Abstract

Leptin action on its receptor (LEPR) stimulates energy expenditure and reduces food intake, thereby lowering body weight. One leptin-sensitive target cell mediating these effects on energy balance is the proopiomelanocortin (POMC) neuron. Recent evidence suggests that the action of leptin on POMC neurons regulates glucose homeostasis independently of its effects on energy balance. Here, we have dissected the physiological impact of direct leptin action on POMC neurons using a mouse model in which endogenous LEPR expression was prevented by a LoxP-flanked transcription blocker (loxTB), but could be reactivated by Cre recombinase. Mice homozygous for the Lepr loxTB allele were obese and exhibited defects characteristic of LEPR deficiency. Reexpression of LEPR only in POMC neurons in the arcuate nucleus of the hypothalamus did not reduce food intake, but partially normalized energy expenditure and modestly reduced body weight. Despite the moderate effects on energy balance and independent of changes in body weight, restoring LEPR in POMC neurons normalized blood glucose and ameliorated hepatic insulin resistance, hyperglucagonemia, and dyslipidemia.Collectively, these results demonstrate that direct leptin action on POMC neurons does not reduce food intake, but is sufficient to normalize glucose and glucagon levels in mice otherwise lacking LEPR. IntroductionLeptin is an adipose-derived hormone that acts on its cognate receptors (LEPR) expressed by multiple neuronal groups in distinct areas of the brain (1). The canonical effect of leptin action in the brain is to regulate food intake and energy expenditure and thus body weight (2-4). In addition, leptin regulates several other physiological processes, including hepatic glucose production, insulin action, and glucagon levels (5-10). It is still unclear, however, which neurons mediate the varied physiological effects of leptin.One population of neurons targeted by leptin is proopiomelanocortin (POMC) cells in the arcuate nucleus of the hypothalamus (ARH) and nucleus of the solitary tract (NTS) (2, 3). Leptin action on POMC neurons in the ARH is considered a prototypical site of action in the control of energy balance. This view is partly based on results showing that loss of LEPR in POMC neurons increases body weight (8,11,12). Conversely, LEPR reexpression in the ARH (13), overexpression in the ARH (14-17), and transgenic expression in POMC neurons (18) lower body weight. Interestingly, these latter studies also show lowered blood glucose, suggesting that leptin-sensitive POMC neurons in the ARH directly modulate metabolism (13-18). In the current study, we developed what we believe to be a novel LEPR-null mouse model in which endogenous LEPR expression can be reexpressed in cells that normally express leptin receptors. Here, we reexpress LEPR only in POMC neurons to delineate the physiological effects on energy and metabolic homeostasis.

Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis

“…Previous studies have shown that insulin-mediated suppression of endogenous glucose production and stimulation of glucose disposal are identical in POMC-cre mice and their WT littermates (27). These data demonstrate that expression of the POMC-cre transgene does not independently affect clamp data.…”

Neuroendocrine control of satiation

“…Selective loss of 5HT-2CR signaling in POMC neurons resulted in hyperphagia and sensitization to dietinduced obesity and blunted the effects of D-fenfluramine and mCPP to suppress eating [264]. These data support the role of POMC neurons in the arcuate nucleus in the control of eating, in contrast to the demonstration that leptin receptor signaling via POMC neurons did not affect eating, only energy expenditure [255,265]. It is important to note that 5HT-2CR and leptin receptors are expressed by anatomically and functionally distinct POMC neurons in the arcuate nucleus, but these populations converge on similar second-order neurons, including those expressing MC4R [228,229].…”

Functional human antibody CDR fusions as long-acting therapeutic endocrine agonists

“…It is known that leptin functions by activating leptin receptors located in the central nervous system and peripheral tissues (45,46). We therefore analyzed whether hLeptin-CDR3H-coil-Herceptin up-regulated gene expression in liver and hypothalamus at multiple time points by quantitative PCR in mice treated with the fusion protein ( Table 2).…”