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

Abstract

The G protein G s α is essential for hormone-stimulated cAMP generation and is an important metabolic regulator. We investigated the role of liver G s -signaling pathways by developing mice with liver-specific G s α 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 G s -signaling pathways in glucose and lipid regulation, which may prove useful in designing new therapeutic targets for diabetes and obesity.

A missense mutation in the non-neural G-protein α-subunit isoforms modulates susceptibility to obesity

“…Gsa has been shown to be involved in the regulation of the production of cAMP; 18,19 it has also been proposed that XLas is an antagonist of Gsa. For example, this may mean that Gsa is responsible for the production of cAMP and XLas for suppression of cAMP levels.…”

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

“…Consistent with the effect of RIαB, liver-specific knockout of Gsα in mice leads to improved glucose tolerance and increased insulin sensitivity in liver and skeletal muscle. These mice also had increased glycogen content and decreased expression of gluconeogenic genes in the liver, accompanied by hypoglycemia and more than 100-fold higher blood glucagon levels compared with controls (Chen et al 2005b), indicating a condition of glucagon resistance. Recently, it was shown that mice with deficiency of the RIIα subunit of PKA had decreased PKA activity in the liver and showed resistance to diet-induced insulin resistance and diabetes (London et al 2014).…”

β cell-specific deficiency of the stimulatory G protein α-subunit G s α leads to reduced β cell mass and insulin-deficient diabetes

“…Immunoblots of tissue extracts, using a G s ␣-specific antibody, were performed as described in ref. 34. Mice were genotyped by PCR as described in ref.…”