The contribution of visceral fat to improved insulin signaling in Ames dwarf mice

Abstract

Ames dwarf (Prop1(df), df/df) mice are characterized by growth hormone (GH), prolactin, and thyrotropin deficiency, remarkable extension of longevity and increased insulin sensitivity with low levels of fasting insulin and glucose. Plasma levels of anti-inflammatory adiponectin are increased in df/df mice, while pro-inflammatory IL-6 is decreased in plasma and epididymal fat. This represents an important shift in the balance between pro- and anti-inflammatory adipokines in adipose tissue, which was not exposed to GH signals during development or adult life. To determine the role of adipose tissue in the control of insulin signaling in these long-living mutants, we examined the effects of surgical removal of visceral (epididymal and perinephric) adipose tissue. Comparison of the results obtained in df/df mice and their normal (N) siblings indicated different effects of visceral fat removal (VFR) on insulin sensitivity and glucose tolerance. The analysis of the expression of genes related to insulin signaling indicated that VFR improved insulin action in skeletal muscle in N mice. Interestingly, this surgical intervention did not improve insulin signaling in df/df mice skeletal muscle but caused suppression of the signal in subcutaneous fat. We conclude that altered profile of adipokines secreted by visceral fat of Ames dwarf mice may act as a key contributor to increased insulin sensitivity and extended longevity of these animals.

Keywords: Ames dwarf; adiponectin; adipose tissue; insulin; obesity.

Figure 1

Effect of VFR on glucose tolerance and whole-body insulin sensitivity. (A, B, C, D) Results of glucose tolerance test (GTT) and insulin tolerance test (ITT). (E) Effect of VFR on fasting blood glucose levels. (F) Effect of VFR on plasma insulin levels. (G) Insulin sensitivity measured by HOMA analysis. Different letters represent statistical significance (P < 0.05). $, *, and # represent statistical significance between N sham and N VFR, df/df sham and df/df VFR, N Sham and df/df sham, respectively.

Figure 2

Differential gene expression upon VFR in skeletal muscle of N and df/df mice. Different letters represent statistical significance (P < 0.05).

Figure 3

Effect of VFR on gene expression in subcutaneous fat. Different letters represent statistical significance (P < 0.05).

Figure 4

Gene expression levels in epididymal fat and adipokines levels in circulation. (A, B, C) Expression of genes promoting insulin sensitivity in epididymal fat. (D) Expression of TNFα transcript in epididymal fat. (E, F) Adiponectin levels in circulation and in different fat pads. (G, H) IL-6 protein levels in EF and serum. Different letters represent statistical significance (P < 0.05)

Figure 5

Proposed mechanisms of extended longevity in df/df mice. GH-deficient df/df mice are very insulin sensitive with low levels of glucose and insulin in circulation. These mutant mice also have high levels of adiponectin and decreased levels of IL-6 in circulation. Due to GH deficiency, df/df mice have very low IGF-1 in circulation and, thus, a decreased incidence of cancer. All these findings taken together could lead to a delayed rate of aging and, thus, an extension of longevity of df/df mice.