Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ

Abstract

The serine/threonine kinase Akt/PKB plays key roles in the regulation of cell growth, survival, and metabolism. It remains unclear, however, whether the functions of individual Akt/PKB isoforms are distinct. To investigate the function of Akt2/PKBβ, mice lacking this isoform were generated. Both male and female Akt2/PKBβ-null mice exhibit mild growth deficiency and an age-dependent loss of adipose tissue or lipoatrophy, with all observed adipose depots dramatically reduced by 22 weeks of age. Akt2/PKBβ-deficient mice are insulin resistant with elevated plasma triglycerides. In addition, Akt2/PKBβ-deficient mice exhibit fed and fasting hyperglycemia, hyperinsulinemia, glucose intolerance, and impaired muscle glucose uptake. In males, insulin resistance progresses to a severe form of diabetes accompanied by pancreatic β cell failure. In contrast, female Akt2/PKBβ-deficient mice remain mildly hyperglycemic and hyperinsulinemic until at least one year of age. Thus, Akt2/PKBβ-deficient mice exhibit growth deficiency similar to that reported previously for mice lacking Akt1/PKBα, indicating that both Akt2/PKBβ and Akt1/PKBα participate in the regulation of growth. The marked hyperglycemia and loss of pancreatic β cells and adipose tissue in Akt2/PKBβ-deficient mice suggest that Akt2/PKBβ plays critical roles in glucose metabolism and the development or maintenance of proper adipose tissue and islet mass for which other Akt/PKB isoforms are unable to fully compensate.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice

“…The presence of steatorrhea, the decrease in serum amylase activity, as well as the histological findings, indicate a concomitant exocrine insufficiency. Interestingly, the diabetic phenotype is more severe in male mice than in female mice lacking E2F1 and E2F2, similar to what has been reported in other animal models such as Cdk4-deficient mice (26) or Akt2-deficient mice (27); it suggests that the control of glucose metabolism in these mice is finely tuned by gender-specific factors.…”

Preproghrelin expression is a key target for insulin action on adipogenesis

“…This fact appears to be a consequence of the AKT activation by both AG and obestatin in adipose tissue (Lodeiro et al 2009, Gurriaran-Rodriguez et al 2010. There is strong evidence, including results obtained from genetic mouse models, supporting the concept that AKT is a key node for regulation of the transcriptional program required for adipogenesis (Cho et al 2001, Garofalo et al 2003, Xu et al 2004, Manning & Cantley 2007, Berggreen et al 2009, Zhang et al 2009. Interestingly, knockdown experiments by preproghrelin siRNA displayed defective adipocyte differentiation.…”

Defects in secretion, aggregation, and thrombus formation in platelets from mice lacking Akt2

“…Akt2 is highly expressed in pancreatic β cells, skeletal muscle, and brown fat (26,27). Akt2 -/-mice produced by two different groups are hyperglycemic, hyperinsulinemic, and have defects in insulin responses (18,28). Those produced by Cho et al exhibit a compensatory increase in pancreatic β cell mass, while those studied by Garofalo et al display an age-dependent loss of adipose tissue, and some Akt2 -/-males develop more severe hyperglycemia due to β cell failure.…”