Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gsα deficiency
Min Chen, … , William Jou, Lee S. Weinstein
Min Chen, … , William Jou, Lee S. Weinstein
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3217-3227. https://doi.org/10.1172/JCI24196.
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Research Article Metabolism

Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gsα deficiency

Abstract

The G protein Gsα is essential for hormone-stimulated cAMP generation and is an important metabolic regulator. We investigated the role of liver Gs-signaling pathways by developing mice with liver-specific Gsα deficiency (LGsKO mice). LGsKO mice had increased liver weight and glycogen content and reduced adiposity, whereas survival, body weight, food intake, and metabolic rates at ambient temperature were unaffected. LGsKO mice had increased glucose tolerance with both increased glucose-stimulated insulin secretion and increased insulin sensitivity in liver and muscle. Fed LGsKO mice were hypoglycemic and hypoinsulinemic, with low expression of hepatic gluconeogenic enzymes and PPARγ coactivator–1. However, LGsKO mice maintained normal fasting glucose and insulin levels, probably due to prolonged breakdown of glycogen stores and possibly increased extrahepatic gluconeogenesis. Lipid metabolism was unaffected in fed LGsKO mice, but fasted LGsKO mice had increased lipogenic and reduced lipid oxidation gene expression in liver and increased serum triglyceride and FFA levels. LGsKO mice had very high serum glucagon and glucagon-like peptide–1 levels and pancreatic α cell hyperplasia, probably secondary to hepatic glucagon resistance and/or chronic hypoglycemia. Our results define novel roles for hepatic Gs-signaling pathways in glucose and lipid regulation, which may prove useful in designing new therapeutic targets for diabetes and obesity.

Authors

Min Chen, Oksana Gavrilova, Wei-Qin Zhao, Annie Nguyen, Javier Lorenzo, Laura Shen, Lisa Nackers, Stephanie Pack, William Jou, Lee S. Weinstein

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Figure 1

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Generation of LGsKO mice. (A) The upstream portion of the wild-type Gnas...
Generation of LGsKO mice. (A) The upstream portion of the wild-type Gnas allele (E1+) including alternative first exon 1A and Gsα exons 1, 2, and 3 is shown at the top, with the positions of the 5′ and 3′ probes used for Southern blot analysis shown above. The scale is in kilobases, with position 0 being the Gsα translational start site. The E1neo-fl allele is shown below E1+, with loxP sites represented as triangles. E1neo-fl mice were mated with EIIa-cre mice to generate mice with the E1fl allele. Repeated mating of E1fl and Alb-cre–transgenic mice produced LGsKO (E1fl/flAlb-cre+) mice with liver-specific deletion of Gsα exon 1 (E1–) in both alleles. S, SacI; Bg, BglII; Neo, neomycin resistance gene. (B) Southern blot analysis of founder mice (2 left lanes) or offspring of E1neo-fl mice crossed with EIIa-cre mice (2 right lanes) after SacI digestion and hybridization with the 5′ probe. Genotypes are indicated above each lane. (C) Immunoblot analysis of protein extracts (60 μg/lane) of various tissues from E1+/+, E1fl/fl, and LGsKO mice, using a Gsα-specific antibody. The doublet represents the long and short forms of Gsα produced by alternative splicing of exon 3. (D) Immunoblot of liver (left) and kidney (right) extracts from control (C) and LGsKO mice (L) with anti–phospho-CREB (CREB-P; top row) and anti-CREB Abs (bottom row). Pairs are indicated by the lines above.