A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity
Caroline E. Geisler,
Susma Ghimire,
Stephanie M. Bruggink,
Kendra E. Miller,
Savanna N. Weninger,
Jason M. Kronenfeld,
Jun Yoshino,
Samuel Klein,
Frank A. Duca,
Benjamin J. Renquist
Affiliations
Caroline E. Geisler
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Susma Ghimire
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Stephanie M. Bruggink
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Kendra E. Miller
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Savanna N. Weninger
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Jason M. Kronenfeld
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Jun Yoshino
Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
Samuel Klein
Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
Frank A. Duca
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA
Benjamin J. Renquist
School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ 85721, USA; Corresponding author
Summary: Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) 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, homeostatic model assessment for insulin resistance (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.
