POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels

Caron, Alexandre; Lemko, Heather M. Dungan; Castorena, Carlos M.; Fujikawa, Teppei; Lee, Syann; Lord, Caleb C.; Ahmed, Newaz; Lee, Charlotte E.; Holland, William L.; Liu, Chen; Elmquist, Joel K.

doi:10.7554/elife.33710

Cited by 97 publications

(80 citation statements)

References 86 publications

(164 reference statements)

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“…POMC neurons localized to the hypothalamus and to the hindbrain are essential for energy homeostasis (Mercer et al 2013, Gautron et al 2015, Dores et al 2016, Toda et al 2017, Caron et al 2018 (Fig. 1).…”

Section: Pomc Neurons Localized In the Hypothalamus And Hindbrain Arementioning

confidence: 99%

The melanocortin pathway and control of appetite-progress and therapeutic implications

Baldini

Phelan

2019

Journal of Endocrinology

185

125

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The initial discovery thatob/obmice become obese because of a recessive mutation of the leptin gene has been crucial to discover the melanocortin pathway to control appetite. In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the ‘starved state’ activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake. This initial understanding of the melanocortin pathway has recently been implemented by the description of the complex neuronal circuit that controls the activity of POMC, AgRP/NPY and MC4R neurons and downstream signaling by these neurons. This review summarizes the progress done on the melanocortin pathway and describes how obesity alters this pathway to disrupt energy homeostasis. We also describe progress on how leptin and insulin receptors signal in POMC neurons, how MC4R signals and how altered expression and traffic of MC4R change the acute signaling and desensitization properties of the receptor. We also describe how the discovery of the melanocortin pathway has led to the use of melanocortin agonists to treat obesity derived from genetic disorders.

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Section: Pomc Neurons Localized In the Hypothalamus And Hindbrain Arementioning

confidence: 99%

The melanocortin pathway and control of appetite-progress and therapeutic implications

Baldini

Phelan

2019

Journal of Endocrinology

185

125

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“…In mice, disruption of SRC-1 in Pomc neurons led to increased food intake, weight gain on a HFD and impaired the acute anorectic response to leptin administration demonstrating the physiological relevance of this molecular interaction. The modest degree of obesity in these mice was comparable to that seen with inactivation of STAT3 in Pomc neurons 9 and studies demonstrating that direct leptin action on Pomc neurons accounts for a proportion of leptin's effects on body weight 19,20,25,26 . The obesity seen in SRC-1 deletion or mutant mice was less severe than that see in mice deficient in Pomc 27 or melanocortin 4 receptor 28 in keeping with SRC-1's role as a modulator of Pomc expression.…”

Section: Discussionmentioning

confidence: 58%

“…Recent evidence indicates that loss of leptin receptors in Pomc neurons does not affect body weight in chow-fed mice 19,20 . In line with these reports, we show that loss of SRC-1 in Pomc neurons produced minor effects on energy balance in chow-fed male mice.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that the SRC-1-pSTAT3 interaction is downstream of leptin-STAT3 signaling, and contributes to the acute anorectic effects of leptin. Notably, the effects of leptin on 4 and 24 h food intake were not significantly altered in pomcSRC-1-KO mice ( Supplementary Figure 2a-b), presumably because the anorectic effects of leptin after the first hour are mediated by other leptinresponsive neurons or other signaling pathways 19,20 .…”

Section: Src-1 Interacts With Pstat3 To Stimulate Pomc Expressionmentioning

confidence: 98%

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Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Yang¹,

AA²,

Zhu³

et al. 2019

ESPE

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Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1 L1376P ), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss. 1 1234567890():,; * Fig. 1 SRC-1 potentiates STAT3-induced Pomc expression. Numbers of mice/repeats in each group are indicated; data are presented as mean ± SEM and compared using T-tests or two-way ANOVA followed by post hoc Sidak tests (#). a Pomc and Socs3 mRNA levels in hypothalami from 16-week old SRC-1-KO and WT control littermates (n = 7/8); **P < 0.01. b ChIP assays detecting pSTAT3 binding on Pomc promoters in hypothalami from male SRC-1-KO and control littermates 30 min after leptin injections (5 mg/kg, i.p.): site 1, −998 to −989; site 2, −361 to −353; site 3, −76 to −68 upstream of Pomc (n = 3/ 4); *P < 0.05. c, d Effects of overexpressed constitutively active STAT3 and SRC-1 on Pomc-(c) or Socs3-luciferase activity (d) in Neuro2A cells (n = 5-9independent experiments). ***P < 0.001 vs. empty vectors; ### P < 0.001 vs. STAT3 alone (#). e Change (Δ) in body weight after male control and pomcSRC-1-KO mice were switched onto a HFD at day 97 (n = 6/9); *P < 0.05 and **P < 0.01 (#). f Fat mass and lean mass measured 28 days after HFD feeding (n = 6/9); *P < 0.05. g Energy intake measured by CLAMS chambers in 12-week old male mice matched for body weight, lean mass, and fat mass. Mice were subjected to a 2-day-chow-2-day-HFD protocol, and chow was replaced by HFD before the onset of dark cycle on day 3. Energy intake was averaged for 2-day chow feeding period and for 2-day HFD feeding period (n = 7/8); *P < 0.05. h Cumulative HFD intake measured in 12-week old male mice singly housed in home cages (n = 10/14); *P < 0.05 (#). i Change in body weight after control and MpomcSRC-1-KO mice were switched on a HFD at the age of day 84 (n = 8); *P < 0.05 (#). j Fat mass and lean mass measured 30 days after HFD feeding (n = 8); *P < 0.05. k Cumulative HFD intake measured in 12-week old male mice (n = 6/7); *P < 0.05 (#), **P < 0.01. Source data are provided as Source Data Fig. 1 ARTICLE NATURE COMMUNICATIONS | https://doi.

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“…Previous studies largely focused on its role in peripheral organs such as the pancreatic islets and the liver 27 . However, given the importance of POMC neurons in coordinating glucose metabolism 28 , it is possible that these neurons may serve as a critical node where Tcf7l2 programs glucose homeostasis at critical developmental periods. Furthermore, the nuclear receptor Nr5a1 (also known as Steroidogenic factor 1, SF1) has been known as a selective marker for VMH neurons during development 29 .…”

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confidence: 99%

Transcriptomic Profiling of Developing Melanocortin Neurons Reveals a Role for Prdm12 in Energy Balance

Chen

Wyler

et al. 2019

Preprint

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The hypothalamus is a critical regulator of many physiological processes essential for life. In the adult brain, each anatomically-defined hypothalamic nucleus consists of functionally heterogeneous neuronal subpopulations that dictate distinct survival behaviors. Nevertheless, how rich neuronal identities are established in the developing hypothalamus remains poorly understood.Despite their opposing actions on food intake, POMC and NPY/AgRP neurons in the arcuate nucleus of the hypothalamus (ARH) are derived from the same progenitors that give rise to ARH neurons. However, the mechanism whereby common neuronal precursors subsequently adopt either the anorexigenic (POMC) or the orexigenic (NPY/AgRP) identity remains elusive.We hypothesize that POMC and NPY/AgRP cell fates are specified and maintained by distinct intrinsic factors. In search of them, we profiled the transcriptomes of developing POMC and NPY/AgRP neurons with whole-genome RNA sequencing (RNA-seq). Moreover, cell-type-specific transcriptomic analyses revealed transcription regulators that are selectively enriched in either population, but whose developmental functions are unknown in these neurons.Among them, we found the expression of the PR domain-containing factor 12 (Prdm12) was enriched in POMC neurons but was absent in NPY/AgRP neurons. Selective ablation of Prdm12 in postmitotic POMC neurons led to early-onset obesity, accelerated linear growth, as well as impaired glucose tolerance, which recapitulates symptoms of POMC/MC4R deficiency in humans. These findings, therefore, establish a previously-unrecognized role for Prdm12 in energy balance. Furthermore, the combination of cell-type-specific genomic and genetic analyses provides a means to dissect cellular and functional diversity in the developing hypothalamus as well as the developmental origins of diverse survival behaviors.

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POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels

Cited by 97 publications

References 86 publications

The melanocortin pathway and control of appetite-progress and therapeutic implications

The melanocortin pathway and control of appetite-progress and therapeutic implications

Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Transcriptomic Profiling of Developing Melanocortin Neurons Reveals a Role for Prdm12 in Energy Balance

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