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Overexpression of Smad7 in hypothalamic POMC neurons disrupts glucose balance by attenuating central insulin signaling.

ABSTRACT: OBJECTIVE:Although the hypothalamus is crucial for peripheral metabolism control, the signals in specific neurons involved remain poorly understood. The aim of our current study was to explore the role of the hypothalamic gene mothers against decapentaplegic homolog 7 (Smad7) in peripheral glucose disorders. METHODS:We studied glucose metabolism in high-fat diet (HFD)-fed mice and middle-aged mice with Cre-mediated recombination causing 1) overexpression of Smad7 in hypothalamic proopiomelanocortin (POMC) neurons, 2) deletion of Smad7 in POMC neurons, and 3) overexpression of protein kinase B (AKT) in arcuate nucleus (ARC) in Smad7 overexpressed mice. Intracerebroventricular (ICV) cannulation of insulin was used to test the hypothalamic insulin sensitivity in the mice. Hypothalamic primary neurons were used to investigate the mechanism of Smad7 regulating hypothalamic insulin signaling. RESULTS:We found that Smad7 expression was increased in POMC neurons in the hypothalamic ARC of HFD-fed or middle-aged mice. Furthermore, overexpression of Smad7 in POMC neurons disrupted the glucose balance, and deletion of Smad7 in POMC neurons prevented diet- or age-induced glucose disorders, which was likely to be independent of changes in body weight or food intake. Moreover, the effect of Smad7 was reversed by overexpression of AKT in the ARC. Finally, Smad7 decreased AKT phosphorylation by activating protein phosphatase 1c in hypothalamic primary neurons. CONCLUSIONS:Our results demonstrated that an excess of central Smad7 in POMC neurons disrupts glucose balance by attenuating hypothalamic insulin signaling. In addition, we found that this regulation was mediated by the activity of protein phosphatase 1c.

SUBMITTER: Yuan F

PROVIDER: S-EPMC7551358 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Overexpression of Smad7 in hypothalamic POMC neurons disrupts glucose balance by attenuating central insulin signaling.

Yuan Feixiang F Yin Hanrui H Deng Yalan Y Jiao Fuxin F Jiang Haizhou H Niu Yuguo Y Chen Shanghai S Ying Hao H Zhai Qiwei Q Chen Yan Y Guo Feifan F

Molecular metabolism 20200922

<h4>Objective</h4>Although the hypothalamus is crucial for peripheral metabolism control, the signals in specific neurons involved remain poorly understood. The aim of our current study was to explore the role of the hypothalamic gene mothers against decapentaplegic homolog 7 (Smad7) in peripheral glucose disorders.<h4>Methods</h4>We studied glucose metabolism in high-fat diet (HFD)-fed mice and middle-aged mice with Cre-mediated recombination causing 1) overexpression of Smad7 in hypothalamic p ...[more]

PMID: 32971298

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Project description:ObjectiveThe long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, stimulates insulin secretion and efficiently suppresses food intake to reduce body weight. As such, liraglutide is growing in popularity in the treatment of diabetes and chronic weight management. Within the brain, liraglutide has been shown to alter the activity of hypothalamic proopiomelanocortin (POMC) and Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons. Moreover, the acute activities of POMC and NPY neurons have been directly linked to feeding behavior, body weight, and glucose metabolism. Despite the increased usage of liraglutide and other GLP-1 analogues as diabetic and obesity interventions, the cellular mechanisms by which liraglutide alters the activity of metabolically relevant neuronal populations are poorly understood.MethodsIn order to resolve this issue, we utilized neuron-specific transgenic mouse models to identify POMC and NPY neurons for patch-clamp electrophysiology experiments.ResultsWe found that liraglutide directly activated arcuate POMC neurons via TrpC5 channels, sharing a similar mechanistic pathway to the adipose-derived peptide leptin. Liraglutide also indirectly increases excitatory tone to POMC neurons. In contrast, liraglutide inhibited NPY/AgRP neurons through post-synaptic GABAA receptors and enhanced activity of pre-synaptic GABAergic neurons, which required both TrpC5 subunits and K-ATP channels. In support of an additive role of leptin and liraglutide in suppressing food intake, leptin potentiated the acute effects of liraglutide to activate POMC neurons. TrpC5 subunits in POMC neurons were also required for the intact pharmacological effects of liraglutide on food intake and body weight. Thus, the current study adds to recent work from our group and others, which highlight potential mechanisms to amplify the effects of GLP-1 agonists in vivo. Moreover, these data highlight multiple sites of action (both pre- and post-synaptic) for GLP-1 agonists on this circuit.ConclusionsTaken together, our results identify critical molecular mechanisms linking GLP-1 analogues in arcuate POMC and NPY/AgRP neurons with metabolism.

Project description:ObjectiveHypothalamic arcuate proopiomelanocortin (Arc-POMC) neurons are involved in different physiological processes such as the regulation of energy balance, glucose homeostasis, and stress-induced analgesia. Since these neurons heterogeneously express different biological markers and project to many hypothalamic and extrahypothalamic areas, it is proposed that Arc-POMC neurons could be classified into different subpopulations having diverse physiological roles. The aim of the present study was to characterize the contribution of the subpopulation of Arc-POMC neurons cosecreting gamma-aminobutyric acid (GABA) neurotransmitter in the control of energy balance.MethodsArc-Pomc expression restricted to GABAergic-POMC neurons was achieved by crossing a reversible Pomc-deficient mouse line (arcPomc-) with a tamoxifen-inducible Gad2-CreER transgenic line. Pomc expression was rescued in the compound arcPomc-/-:Gad2-CreER female and male mice by tamoxifen treatment at postnatal days 25 (P25) or 60 (P60), and body weight, daily food intake, fasting glycemia, and fasting-induced hyperphagia were measured. POMC recovery was quantified by immunohistochemistry and semiquantitative RT-PCR. Neuropeptide Y (NPY) and GABAergic neurons were identified by in situ hybridization. Arc-POMC neurons projecting to the dorsomedial hypothalamic nucleus (DMH) were studied by stereotactic intracerebral injection of fluorescent retrobeads into the DMH.ResultsTamoxifen treatment of arcPomc-/-:Gad2-CreER mice at P60 resulted in Pomc expression in ∼23-25% of Arc-POMC neurons and ∼15-23% of Pomc mRNA levels, compared to Gad2-CreER control mice. Pomc rescue in GABAergic-POMC neurons at P60 normalized food intake, glycemia, and fasting-induced hyperphagia, while significantly reducing body weight. Energy balance was also improved in arcPomc-/-:Gad2-CreER mice treated with tamoxifen at P25. Distribution analysis of rescued POMC immunoreactive fibers revealed that the DMH is a major target site of GABAergic-POMC neurons. Further, the expression of the orexigenic neuropeptide Y (NPY) in the DMH was increased in arcPomc-/- obese mice but was completely restored after Pomc rescue in arcPomc-/-:Gad2-CreER mice. Finally, we found that ∼75% of Arc-POMC neurons projecting to the DMH are GABAergic.ConclusionsIn the present study, we show that the expression of Pomc in the subpopulation of Arc-GABAergic-POMC neurons is sufficient to maintain normal food intake. In addition, we found that DMH-NPY expression is negatively correlated with Pomc expression in GABAergic-POMC neurons, suggesting that food intake may be regulated by an Arc-GABAergic-POMC → DMH-NPY pathway.

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Overexpression of Smad7 in hypothalamic POMC neurons disrupts glucose balance by attenuating central insulin signaling.

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Overexpression of Smad7 in hypothalamic POMC neurons disrupts glucose balance by attenuating central insulin signaling.

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