Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice

Abstract

Leptin is an adipose-derived hormone that signals to inform the brain of nutrient status; loss of leptin signaling results in marked hyperphagia and obesity. Recent work has identified several groups of neurons that contribute to the effects of leptin to regulate energy balance, but leptin receptors are distributed throughout the brain, and the function of leptin signaling in discrete neuronal populations outside of the hypothalamus has not been defined. In the current study, we produced mice in which the long form of the leptin receptor (Lepr) was selectively ablated using Cre-recombinase selectively expressed in the hindbrain under control of the paired-like homeobox 2b (Phox2b) promoter (Phox2b Cre Lepr flox/flox mice). In these mice, Lepr was deleted from glucagonlike 1 peptide-expressing neurons resident in the nucleus of the solitary tract. Phox2b Cre Lepr flox/flox mice were hyperphagic, displayed increased food intake after fasting, and gained weight at a faster rate than wild-type controls. Paradoxically, Phox2b Cre Lepr flox/flox mice also exhibited an increased metabolic rate independent of a change in locomotor activity that was dependent on food intake, and glucose homeostasis was normal. Together, these data support a physiologically important role of direct leptin action in the hindbrain. IntroductionLeptin, an adipocyte-derived hormone, circulates at concentrations that reflect overall fat mass and informs the body of nutritional status (1-3). Loss of leptin or leptin receptor expression, in both humans and animal models (3-5), leads to a striking elevation in food intake. This is accompanied by decreased sympathetic tone, energy expenditure, locomotor activity, and body temperature that produces marked obesity and alterations in glucose homeostasis. Deletion of leptin receptors in the CNS recapitulates the effects of leptin deficiency on metabolic homeostasis (6). In addition, several studies have found that selective perturbation of leptin action within populations of medial basal hypothalamic neurons accounts for some of the effects of leptin in the regulation of energy balance (7-11). For example, leptin receptor deletion in proopioid melanocortin (POMC) arcuate neurons and steroidogenic factor 1 neurons in the ventromedial hypothalamus (VMH) produces modest obesity (7, 10). Interestingly, the metabolic alterations observed in animals with these hypothalamic manipulations of leptin expression were substantially less than those observed in the global receptor null, suggesting that the actions of leptin in the CNS are distributed across neuronal populations in addition to those in the hypothalamus. This is not surprising since leptin receptor expression has been observed in nuclei outside of the medial basal hypothalamus in cell populations implicated in the regulation of food intake and metabolic rate (12)(13)(14).In particular, leptin receptor expression in the nucleus of the solitary tract (NTS) has been suggested to affect food intake through the modulation of meal size as a result of the p...

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FOXO1 in the ventromedial hypothalamus regulates energy balance

“…Several reports suggest that distinct neuronal populations are differentially regulated by key metabolic signals (10)(11)(12). However, the metabolic functions of FOXO1 in other hypothalamic neurons have yet to be delineated.…”

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