# Aged Male Mice Remain Glucose Tolerant Despite Increased Energy Storage Efficiency Favoring Diet‐Induced Obesity

## TL;DR

Older male mice can store more fat without developing glucose intolerance, but this makes them more prone to obesity.

## Contribution

The study reveals that aged mice have increased fat storage efficiency and reduced lipid turnover, which protects against glucose intolerance but increases obesity risk.

## Key findings

- Old mice on a high-fat diet gained more fat mass but remained glucose tolerant.
- Old mice showed reduced lipid turnover in visceral fat and increased plasticity in subcutaneous fat.
- Increased fat storage efficiency in old mice did not protect against weight loss during calorie restriction.

## Abstract

Obesity and aging are converging health challenges, contributing to morbidity in older populations. However, the specific contribution of age to susceptibility to obesity is unclear. This study examined the impact of age on susceptibility to diet‐induced obesity (DIO) and calorie restriction (CR) in male mice. Young (2–3 months) and old (17–24 months) lean C57BL/6J male mice were fed a standard chow diet (CD) or a high‐fat diet (HFD) for 28 days, then underwent 18 days of CR. We monitored body weight, body composition, energy intake and expenditure, glucose tolerance, and gene expression in metabolically relevant tissues. HFD‐fed old mice exhibited more fat mass gain but, surprisingly, protection from glucose intolerance. In comparison, young controls exhibited resistance to DIO due to reduced calorie storage efficiency. Gene expression analysis suggested reduced plasticity and lipid turnover in visceral adipose tissue but increased subcutaneous adipose tissue plasticity in old mice. The increased energy storage did not protect old mice from body weight loss following CR. Old mice exhibit increased susceptibility to DIO due to near optimal efficiency storing calories as fat. This susceptibility correlates with increased energy storage efficiency and the absence of energy demanding anabolic processes, like lean mass accrual, exhibited by young mice. Despite increased predisposition to obesity, lifelong leanness confers resilient glycemic control to old mice, emphasizing the importance of maintaining a healthy body weight and dietary habits throughout life to mitigate age‐related metabolic risks.

Aging enhances glycemic control during short‐term high‐fat diet but increases vulnerability to obesity due to greater fat storage efficiency, reduced lipid turnover, and increased liver fat. These changes uncouple adiposity from glycemia, sustaining glucose homeostasis while increasing obesity and steatohepatitis risks without protecting against weight loss upon calorie restriction.