Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gs alpha deficiency.
The G protein G(s)alpha 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)alpha 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 PPARgamma 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 alpha 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.
Chen
Min
M
Metabolic Diseases Branch, NIDDK, NIH, Bethesda, Maryland 20892-1752, USA.
Gavrilova
Oksana
O
Zhao
Wei-Qin
WQ
Nguyen
Annie
A
Lorenzo
Javier
J
Shen
Laura
L
Nackers
Lisa
L
Pack
Stephanie
S
Jou
William
W
Weinstein
Lee S
LS
D050154:Adiposity / Q000235:genetics*; D000818:Animals; D004435:Eating / Q000235:genetics; D005215:Fasting / Q000378:metabolism / Q000502:physiology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010101:Oxygen Consumption / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D019205:GTP-Binding Protein alpha Subunits, Gs; D005947:Glucose