The effect of calorie restriction on insulin signaling in skeletal muscle and adipose tissue of Ames dwarf mice

Denise S Wiesenborn,Xu Zhi,Adam Gesing,Michal M Masternak,Andrew Do,Vinal Menon,Zhihui Wang,Andrzej Bartke,Deborah A Altomare

doi:10.18632/aging.100700

Abstract

Long-living Ames dwarf (df/df) mice are homozygous for a mutation of the Prop1(df) gene. As a result, mice are deficient in growth hormone (GH), prolactin (PRL) and thyrotropin (TSH). In spite of the hormonal deficiencies, df/df mice live significantly longer and healthier lives compared to their wild type siblings. We studied the effects of calorie restriction (CR) on the expression of insulin signaling genes in skeletal muscle and adipose tissue of normal and df/df mice. The analysis of genes expression showed that CR differentially affects the insulin signaling pathway in these insulin target organs. Moreover, results obtained in both normal and Ames dwarf mice indicate more direct effects of CR on insulin signaling genes in adipose tissue than in skeletal muscle. Interestingly, CR reduced the protein levels of adiponectin in the epididymal adipose tissue of normal and Ames dwarf mice, while elevating adiponectin levels in skeletal muscle and plasma of normal mice only. In conclusion, our findings suggest that both skeletal muscle and adipose tissue are important mediators of insulin effects on longevity. Additionally, the results revealed divergent effects of CR on expression of genes in the insulin signaling pathway of normal and Ames dwarf mice.

Highlights

Ames dwarf mice are homozygous for a spontaneous recessive mutation of the prophet of pituitary factor-1 (Prop1) gene, which inhibits development of three specific anterior pituitary cell types - somatotrophs, lactotrophs and thyrothrophs [1]
At the age of 3 months, df/df and N male mice were randomly divided into four experimental groups, with 10 animals per group: normal mice with unlimited food access (N-ad libitum (AL)), normal mice subjected to 30% calorie restriction (CR) (NCR), Ames dwarf mice with unlimited food access, Ames dwarf mice subjected to 30% CR
Calorie restriction caused a significant decrease in blood glucose levels in N-CR mice relative to N-AL littermates (P=0.0001) and it led to decreased blood glucose levels in df/df-CR mice compared to df/df-AL (P=0.0151) (Figure 1B)

Summary

Introduction

Ames dwarf (df/df) mice are homozygous for a spontaneous recessive mutation of the prophet of pituitary factor-1 (Prop1) gene, which inhibits development of three specific anterior pituitary cell types - somatotrophs, lactotrophs and thyrothrophs [1] The absence of these cell types in the df/df mice leads to deficiency of growth hormone (GH), prolactin (PRL) and thyrotropin (TSH). Ames dwarf mice phenotypically appear normal at birth but they grow at a slower rate and reach only half of the normal adult body weight, compared to their normal littermates Their sexual maturity is delayed and females are sterile because of PRL deficiency [2, 3].

Objectives

Methods

Results

Conclusion