Caloric Restriction Chronically Impairs Metabolic Programming in Mice

Although obesity rates are rapidly rising, caloric restriction remains one of the few safe therapies. Here we tested the hypothesis that obesity-associated disorders are caused by increased adipose tissue as opposed to excess dietary lipids. Fat mass (FM) of lean C57B6 mice fed a high-fat diet (HFD; FMC mice) was “clamped” to match the FM of mice maintained on a low-fat diet (standard diet [SD] mice). FMC mice displayed improved glucose and insulin tolerance as compared with ad libitum HFD mice (P < 0.001) or SD mice (P < 0.05). These improvements were associated with fewer signs of inflammation, consistent with the less-impaired metabolism. In follow-up studies, diet-induced obese mice were food restricted for 5 weeks to achieve FM levels identical with those of age-matched SD mice. Previously, obese mice exhibited improved glucose and insulin tolerance but showed markedly increased fasting-induced hyperphagia (P < 0.001). When mice were given ad libitum access to the HFD, the hyperphagia of these mice led to accelerated body weight gain as compared with otherwise matched controls without a history of obesity. These results suggest that although caloric restriction on a HFD provides metabolic benefits, maintaining those benefits may require lifelong continuation, at least in individuals with a history of obesity.Caloric restriction (CR) has become a popular recommendation to decrease body weight (BW) (1), achieve metabolic benefits, and potentially increase life expectancy (2–4). Although the benefits of weight loss are undeniable, the optimal method to achieve a healthy weight is the subject of continuing debate. Obesity is accompanied by many comorbidities (5), and it is widely accepted as a causal factor. A current hypothesis suggests that obesity provokes inflammation in adipose tissue (6), leading to the release of proinflammatory mediators into systemic circulation. Rodent studies suggest that consumption of a high-fat diet (HFD) leads to infiltration by T cells (7) and macrophages (8), which likely contributes to inflammation in adipose tissue and the development of obesity-associated diseases such as type 2 diabetes (9).Alternative explanations for the obesity-related comorbidities are based on specific harmful effects of HFDs per se. High-fat foods induce stress in the intestinal epithelium (10) and promote inflammation by absorption of antigenic material from the gut (11,12). Furthermore, HFD feeding increases reactive oxygen species production (13) that preceded obesity (14), suggesting that like sucrose and fructose, dietary lipids may contribute to obesity-associated diseases. In the present experiments we tested the hypothesis that obesity-associated disorders are caused by increased adipose tissue, as opposed to the obesogenic diet. To dissect these possibilities, we isolated body fat mass (FM) from fat intake using a “FM clamp” mouse model (Fig. 1A). In related studies, we asked whether a history of obesity affects future energy metabolism. Published reports suggest that counter-regulatory mechanisms that develop during CR lead to enhanced metabolic efficiency and rapid weight regain (15,16). We thus aimed to distinguish if this metabolic reprogramming is related to prior obesity, dietary fat intake, or having been calorically restricted (Fig. 1A).Open in a separate windowFIG. 1.A: Study design and FM clamping. B: FM was measured by nuclear magnetic resonance technology and did not differ between SD and FMC mice. C: BW of SD, HFD fed, and FMC mice was measured daily. Mice from the SD and HFD group were fed with SD or HFD ad libitum. Mice from the FMC group were fed defined amounts of HFD to match FM to the SD group. D: Absolute food intake was lowest in FMC mice (P < 0.001). E: Caloric intake was similar in FMC and SD mice and highest in mice of the HFD group. All mice are male (n = 16 per group). All data are represented as mean ± SEM. ITT, insulin tolerance test; FI, food intake.