Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity

Objective: Cav3.2, a T-type low voltage-activated calcium channel widely expressed throughout the central nervous system, plays a vital role in neuronal excitability and various physiological functions. However, the effects of Cav3.2 on energy homeostasis remain unclear. Here, we examined the role o...

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Autores principales:	Bing Feng, Jerney Harms, Nirali Patel, Hui Ye, Pei Luo, Valeria Torres Irizarry, Jacob Vidrine, Ann Coulter, Candida J. Rebello, Sangho Yu, Jia Fan, Hans-Rudolf Berthoud, Frank Greenway, Heike Münzberg, Christopher Morrison, Pingwen Xu, Yanlin He
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Cav3.2 GABA neurons Feeding Hypothalamus Obesity Naringenin Internal medicine RC31-1245
Acceso en línea:	https://doaj.org/article/89cb72c470794a56a801b27322cddf59
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spelling	oai:doaj.org-article:89cb72c470794a56a801b27322cddf592021-12-02T05:01:29ZTargeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity2212-877810.1016/j.molmet.2021.101391https://doaj.org/article/89cb72c470794a56a801b27322cddf592021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2212877821002465https://doaj.org/toc/2212-8778Objective: Cav3.2, a T-type low voltage-activated calcium channel widely expressed throughout the central nervous system, plays a vital role in neuronal excitability and various physiological functions. However, the effects of Cav3.2 on energy homeostasis remain unclear. Here, we examined the role of Cav3.2 expressed by hypothalamic GABAergic neurons in the regulation of food intake and body weight in mice and explored the underlying mechanisms. Methods: Male congenital Cana1h (the gene coding for Cav3.2) global knockout (Cav3.2KO) mice and their wild type (WT) littermates were first used for metabolic phenotyping studies. By using the CRISPR-Cas9 technique, Cav3.2 was selectively deleted from GABAergic neurons in the arcuate nucleus of the hypothalamus (ARH) by specifically overexpressing Cas9 protein and Cav3.2-targeting sgRNAs in ARH Vgat (VgatARH) neurons. These male mutants (Cav3.2KO-VgatARH) were used to determine whether Cav3.2 expressed by VgatARH neurons is required for the proper regulation of energy balance. Subsequently, we used an electrophysiological patch-clamp recording in ex vivo brain slices to explore the impact of Cav3.2KO on the cellular excitability of VgatARH neurons. Results: Male Cav3.2KO mice had significantly lower food intake than their WT littermate controls when fed with either a normal chow diet (NCD) or a high-fat diet (HFD). This hypophagia phenotype was associated with increased energy expenditure and decreased fat mass, lean mass, and total body weight. Selective deletion of Cav3.2 in VgatARH neurons resulted in similar feeding inhibition and lean phenotype without changing energy expenditure. These data provides an intrinsic mechanism to support the previous finding on ARH non-AgRP GABA neurons in regulating diet-induced obesity. Lastly, we found that naringenin extract, a predominant flavanone found in various fruits and herbs and known to act on Cav3.2, decreased the firing activity of VgatARH neurons and reduced food intake and body weight. These naringenin-induced inhibitions were fully blocked in Cav3.2KO-VgatARH mice. Conclusion: Our results identified Cav3.2 expressed by VgatARH neurons as an essential intrinsic modulator for food intake and energy homeostasis, which is a potential therapeutic target in the treatment of obesity.Bing FengJerney HarmsNirali PatelHui YePei LuoValeria Torres IrizarryJacob VidrineAnn CoulterCandida J. RebelloSangho YuJia FanHans-Rudolf BerthoudFrank GreenwayHeike MünzbergChristopher MorrisonPingwen XuYanlin HeElsevierarticleCav3.2GABA neuronsFeedingHypothalamusObesityNaringeninInternal medicineRC31-1245ENMolecular Metabolism, Vol 54, Iss , Pp 101391- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cav3.2 GABA neurons Feeding Hypothalamus Obesity Naringenin Internal medicine RC31-1245
spellingShingle	Cav3.2 GABA neurons Feeding Hypothalamus Obesity Naringenin Internal medicine RC31-1245 Bing Feng Jerney Harms Nirali Patel Hui Ye Pei Luo Valeria Torres Irizarry Jacob Vidrine Ann Coulter Candida J. Rebello Sangho Yu Jia Fan Hans-Rudolf Berthoud Frank Greenway Heike Münzberg Christopher Morrison Pingwen Xu Yanlin He Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity
description	Objective: Cav3.2, a T-type low voltage-activated calcium channel widely expressed throughout the central nervous system, plays a vital role in neuronal excitability and various physiological functions. However, the effects of Cav3.2 on energy homeostasis remain unclear. Here, we examined the role of Cav3.2 expressed by hypothalamic GABAergic neurons in the regulation of food intake and body weight in mice and explored the underlying mechanisms. Methods: Male congenital Cana1h (the gene coding for Cav3.2) global knockout (Cav3.2KO) mice and their wild type (WT) littermates were first used for metabolic phenotyping studies. By using the CRISPR-Cas9 technique, Cav3.2 was selectively deleted from GABAergic neurons in the arcuate nucleus of the hypothalamus (ARH) by specifically overexpressing Cas9 protein and Cav3.2-targeting sgRNAs in ARH Vgat (VgatARH) neurons. These male mutants (Cav3.2KO-VgatARH) were used to determine whether Cav3.2 expressed by VgatARH neurons is required for the proper regulation of energy balance. Subsequently, we used an electrophysiological patch-clamp recording in ex vivo brain slices to explore the impact of Cav3.2KO on the cellular excitability of VgatARH neurons. Results: Male Cav3.2KO mice had significantly lower food intake than their WT littermate controls when fed with either a normal chow diet (NCD) or a high-fat diet (HFD). This hypophagia phenotype was associated with increased energy expenditure and decreased fat mass, lean mass, and total body weight. Selective deletion of Cav3.2 in VgatARH neurons resulted in similar feeding inhibition and lean phenotype without changing energy expenditure. These data provides an intrinsic mechanism to support the previous finding on ARH non-AgRP GABA neurons in regulating diet-induced obesity. Lastly, we found that naringenin extract, a predominant flavanone found in various fruits and herbs and known to act on Cav3.2, decreased the firing activity of VgatARH neurons and reduced food intake and body weight. These naringenin-induced inhibitions were fully blocked in Cav3.2KO-VgatARH mice. Conclusion: Our results identified Cav3.2 expressed by VgatARH neurons as an essential intrinsic modulator for food intake and energy homeostasis, which is a potential therapeutic target in the treatment of obesity.
format	article
author	Bing Feng Jerney Harms Nirali Patel Hui Ye Pei Luo Valeria Torres Irizarry Jacob Vidrine Ann Coulter Candida J. Rebello Sangho Yu Jia Fan Hans-Rudolf Berthoud Frank Greenway Heike Münzberg Christopher Morrison Pingwen Xu Yanlin He
author_facet	Bing Feng Jerney Harms Nirali Patel Hui Ye Pei Luo Valeria Torres Irizarry Jacob Vidrine Ann Coulter Candida J. Rebello Sangho Yu Jia Fan Hans-Rudolf Berthoud Frank Greenway Heike Münzberg Christopher Morrison Pingwen Xu Yanlin He
author_sort	Bing Feng
title	Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity
title_short	Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity
title_full	Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity
title_fullStr	Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity
title_full_unstemmed	Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity
title_sort	targeting the t-type calcium channel cav3.2 in gabaergic arcuate nucleus neurons to treat obesity
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/89cb72c470794a56a801b27322cddf59
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Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity

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