Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits

Padilla, Stéphanie L.; Carmody, Jill S.; Zeltser, Lori M.

doi:10.1038/nm.2126

Cited by 262 publications

(314 citation statements)

References 21 publications

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“…This issue has been highlighted by work finding disparate phenotypes in mice with pre-and postnatal ablation of AgRP neurons (55). Recent studies have also reported that multiple lineages of hypothalamic neurons express POMC, including cells that do not express POMC in adult mice (56). Future studies employing an inducible model of cre-recombinase in POMC neurons in the Lepr loxTB mouse are needed to examine these issues.…”

Section: Figurementioning

confidence: 99%

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

et al. 2012

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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.

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Section: Figurementioning

confidence: 99%

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

et al. 2012

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“…Energy-balance neurons were the earliest born, with substantial numbers present at E10.5 that express the neuropeptide POMC ( Figure 1A) shortly after cell-cycle exit (22,23). These immature POMC + neurons do not solely become mature POMC + neurons but also give rise to mature NPY + neurons (24). We confirmed our previous findings that embryonic generation of these energy-balance neurons occurred around E10.5 by counting the number of POMC + immature ARN neurons in developing embryos within the E10.5 gestational window (n = 6).…”

Section: The Hypothalamic Energy-balance Circuit Is Dynamically Remodmentioning

confidence: 99%

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

McNay¹,

Briançon²,

Kokoeva³

et al. 2012

J. Clin. Invest.

280

299

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In the CNS, the hypothalamic arcuate nucleus (ARN) energy-balance circuit plays a key role in regulating body weight. Recent studies have shown that neurogenesis occurs in the adult hypothalamus, revealing that the ARN energy-balance circuit is more plastic than originally believed. Changes in diet result in altered gene expression and neuronal activity in the ARN, some of which may reflect hypothalamic plasticity. To explore this possibility, we examined the turnover of hypothalamic neurons in mice with obesity secondary to either high-fat diet (HFD) consumption or leptin deficiency. We found substantial turnover of neurons in the ARN that resulted in ongoing cellular remodeling. Feeding mice HFD suppressed neurogenesis, as demonstrated by the observation that these mice both generated fewer new neurons and retained more old neurons. This suppression of neuronal turnover was associated with increased apoptosis of newborn neurons. Leptin-deficient mice also generated fewer new neurons, an observation that was explained in part by a loss of hypothalamic neural stem cells. These data demonstrate that there is substantial postnatal turnover of the arcuate neuronal circuitry in the mouse and reveal the unexpected capacity of diet and leptin deficiency to inhibit this neuronal remodeling. This insight has important implications for our understanding of nutritional regulation of energy balance and brain function. IntroductionThe hypothalamus is a critical regulator of energy balance. Lesions of the ventromedial nucleus (1) or arcuate nucleus (ARN) (2) result in obesity, while lesions of the lateral hypothalamic area (3) result in weight loss. Energy-related signals such as leptin (4, 5) are integrated by responsive neurons in the ARN and ventromedial hypothalamus. In particular, leptin stimulates the anorexigenic proopiomelanocortin (POMC) neurons and inhibits orexigenic neuropeptide Y (NPY) neurons. In situations of negative energy balance, reduced leptin levels inhibit the activity of POMC neurons and activate NPY neurons. While this feedback circuit is essential for normal energy homeostasis (see review refs. 6, 7), most obesity is associated with dysregulation of the circuit and leptin resistance (8).Two commonly studied mouse models of obesity, the high-fat diet-induced (HFD-induced) obesity (DIO) model (9) and the more severe obesity arising from the lack of leptin (4, 5), share features such as increased fat mass, hyperglycemia, hyperinsulinemia, and activation of the adrenal axis but are distinct in that DIO mice have elevated peripheral leptin levels and are resistant to both endogenous and exogenous leptin (8). DIO mice also become resistant to centrally administered leptin (10). This phenomenon is reversible, with leptin responsiveness returning several months after cessation of HFD consumption (11).The molecular and cellular mechanisms underlying hypothalamic dysfunction in the context of obesity over long-time frames are still not fully understood. Possible mechanisms include impaired leptin transport acr...

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“…We next asked whether adult-onset loss of serotonin 2C receptors in POMC neurons results in a phenotype similar to that of ablation during development. This is a key issue, because recent work has found that multiple lineages of hypothalamic neurons express POMC, including cells that may not express POMC in adult mice (28). Additionally, recent studies have shown that pre-and postnatal ablation of AgRP neurons results in disparate feeding behavior phenotypes (29).…”

Section: Figurementioning

confidence: 99%

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

Liu²,

et al. 2013

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Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptorexpressing neurons that mediate the effects of serotonin and serotonin 2C receptor agonists on energy and glucose homeostasis are unknown. Here, we show that mice lacking serotonin 2C receptors (Htr2c) specifically in pro-opiomelanocortin (POMC) neurons had normal body weight but developed glucoregulatory defects including hyperinsulinemia, hyperglucagonemia, hyperglycemia, and insulin resistance. Moreover, these mice did not show anorectic responses to serotonergic agents that suppress appetite and developed hyperphagia and obesity when they were fed a high-fat/high-sugar diet. A requirement of serotonin 2C receptors in POMC neurons for the maintenance of normal energy and glucose homeostasis was further demonstrated when Htr2c loss was induced in POMC neurons in adult mice using a tamoxifen-inducible POMC-cre system. These data demonstrate that serotonin 2C receptor-expressing POMC neurons are required to control energy and glucose homeostasis and implicate POMC neurons as the target for the effect of serotonin 2C receptor agonists on weight-loss induction and improved glycemic control.

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Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits

Cited by 262 publications

References 21 publications

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

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

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

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

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