Abstract
Leptin is critical for energy balance, glucose homeostasis, and for metabolic and neuroendocrine adaptations to starvation. A prevalent model predicts that leptin's actions are mediated through pro-opiomelanocortin (POMC) neurons that express leptin receptors (LEPRs). However, previous studies have used prenatal genetic manipulations, which may be subject to developmental compensation. Here, we tested the direct contribution of POMC neurons expressing LEPRs in regulating energy balance, glucose homeostasis and leptin secretion during fasting using a spatiotemporally controlled Lepr expression mouse model. We report a dissociation between leptin's effects on glucose homeostasis versus energy balance in POMC neurons. We show that these neurons are dispensable for regulating food intake, but are required for coordinating hepatic glucose production and for the fasting-induced fall in leptin levels, independent of changes in fat mass. We also identify a role for sympathetic nervous system regulation of the inhibitory adrenergic receptor (ADRA2A) in regulating leptin production. Collectively, our findings highlight a previously unrecognized role of POMC neurons in regulating leptin levels.
Highlights
Pro-opiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) are critical regulators of energy balance and glucose homeostasis (Mercer et al, 2013; Gautron et al, 2015)
We identified an important role for adipose tissue ADRA2A in regulating leptin synthesis
We first assessed the impact of adult deletion of leptin receptors (LEPRs)-expressing POMC neurons on glucose homeostasis
Summary
Pro-opiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) are critical regulators of energy balance and glucose homeostasis (Mercer et al, 2013; Gautron et al, 2015) These neurons consist of a heterogeneous population with respect to neurotransmitters used and the receptors expressed (Hentges et al, 2009; Williams et al, 2010; Lam et al, 2017). Given the role of POMC neurons and leptin in metabolism, a conventional model indicates that a subset of POMC cells that expresses the leptin receptor (LEPR) are mediating the metabolic actions of leptin (Cheung et al, 1997; Balthasar et al, 2005).
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