A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity
A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity
Abstract Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) and associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia, and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, HOMA-IR, T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.
Renquist Benjamin. J.、Ghimire Susma.、Bruggink Stephanie. M.、Miller Kendra E.、Weninger Savanna. N.、Kronenfeld Jason. M.、Yoshino Jun.、Duca Frank. A.、Klein Samuel.、Geisler Caroline. E.
School of Animal and Comparative Biomedical Sciences, University of ArizonaSchool of Animal and Comparative Biomedical Sciences, University of ArizonaSchool of Animal and Comparative Biomedical Sciences, University of ArizonaSchool of Animal and Comparative Biomedical Sciences, University of ArizonaSchool of Animal and Comparative Biomedical Sciences, University of ArizonaSchool of Animal and Comparative Biomedical Sciences, University of ArizonaCenter for Human Nutrition, Washington University School of MedicineSchool of Animal and Comparative Biomedical Sciences, University of ArizonaCenter for Human Nutrition, Washington University School of MedicineSchool of Animal and Comparative Biomedical Sciences, University of Arizona||Perelman School of Medicine, University of Pennsylvania
基础医学生理学生物化学
Renquist Benjamin. J.,Ghimire Susma.,Bruggink Stephanie. M.,Miller Kendra E.,Weninger Savanna. N.,Kronenfeld Jason. M.,Yoshino Jun.,Duca Frank. A.,Klein Samuel.,Geisler Caroline. E..A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity[EB/OL].(2025-03-28)[2025-04-27].https://www.biorxiv.org/content/10.1101/2020.04.02.022699.点此复制
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