Paternal high-fat diet enhances offspring whole-body insulin sensitivity and skeletal muscle insulin signaling early in life.

Leslie A Consitt,Yuriy Slyvka,Felicia V Nowak,Gunjan Saxena,Brian C Clark,Max Friedlander,Yizhu Zhang

doi:10.14814/phy2.13583

Abstract

Evidence suggests that paternal diet can predispose offspring to metabolic dysfunction. Despite this knowledge, little is known regarding the effects of paternal high‐fat feeding on offspring insulin sensitivity. The purpose of this study was to investigate for the first time the effects of paternal high‐fat feeding on whole‐body and skeletal muscle insulin action in young and adult offspring. At 4 weeks of age, founder C57BL6/N males (F0) were fed a high‐fat diet or control diet for 12 weeks and then bred with females on a control diet. Offspring (F1) were euthanized at 6 weeks, 6 months, or 12 months and insulin‐stimulated insulin signaling was measured ex vivo in isolated soleus muscle. At 6 weeks of age, paternal high fat offspring (HFO) had enhanced whole‐body insulin sensitivity (35%, P < 0.05), as well as, increased insulin‐stimulated skeletal muscle phosphorylation of Akt threonine 308 (70%, P < 0.05) and AS160 threonine 642 (80%, P < 0.05) compared to paternal control fed offspring (CFO), despite both offspring groups consuming standard chow. At 6 months of age, HFO had increased percent body fat compared to CFO (74%, P < 0.005) and whole‐body and skeletal muscle insulin signaling normalized to CFO. Body fat was inversely related with insulin signaling in HFO, but not CFO. These findings suggest that paternal high‐fat feeding contributes to enhanced whole‐body and skeletal muscle insulin sensitivity in HFO early in life; however, these benefits are lost by early adulthood, potentially due to premature increases in body fat.

Highlights

Rates of obesity and type 2 diabetes have reached epidemic proportions over the past decade with researchers continuing efforts to elucidate the factors responsible for weight gain and insulin resistance
At 6 months of age, percent body fat was 74% higher (P < 0.005, Fig. 1A), and percent lean mass was 8% lower (P < 0.05, Fig. 1B) in the high fat offspring (HFO) compared to the control fed offspring (CFO), despite offspring being on the same standard diet
Insulin-stimulated AS160 threonine 642 phosphorylation was 80% higher (P < 0.05) in the HFO compared to the CFO at 6 weeks of age; at 12 months of age, phosphorylation was 45% lower (P < 0.05) in the HFO compared to CFO (Fig. 4A)

Summary

Introduction

Rates of obesity and type 2 diabetes have reached epidemic proportions over the past decade with researchers continuing efforts to elucidate the factors responsible for weight gain and insulin resistance. It was recently reported that the offspring of paternal high-fat diet-fed rodents developed increased adiposity as early as 8 weeks of age (Fullston et al 2013; Lecomte et al 2017) and two studies reported the onset of insulin resistance at 16–24 weeks of age (Fullston et al 2013; Masuyama et al 2016) despite the consumption of control chow in the offspring, suggesting the father’s diet prior to conception could predispose offspring to the development of type 2 diabetes. Based on previously published time points, it remains unclear if insulin resistance occurs prior to adulthood and what cellular mechanism(s) may contribute to the insulin resistance in these mice

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