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

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

Molecular Metabolism (Dec 2021)

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

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

Affiliations

Bing Feng: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA
Jerney Harms: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA
Nirali Patel: The Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
Hui Ye: The Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
Pei Luo: The Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
Valeria Torres Irizarry: The Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA
Jacob Vidrine: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA
Ann Coulter: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA
Candida J. Rebello: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA
Sangho Yu: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA
Jia Fan: The Department of Biochemistry and Molecular Biology, Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
Hans-Rudolf Berthoud: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA
Frank Greenway: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA
Heike Münzberg: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA
Christopher Morrison: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA
Pingwen Xu: The Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, 60612, USA; Corresponding author. 835 S Wolcott Ave, MC 613, Chicago, IL, 60612, USA. Fax: +(312)-413-0437.
Yanlin He: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Rd, Baton Rouge, LA, 70808, USA; Corresponding author. 6400 Perkins Road, Basic Science Building, L2024, Baton Rouge, LA, 70808-4124, USA. Fax: +(225)-763-2525.

Journal volume & issue: Vol. 54
p. 101391

Abstract

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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.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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