Mild Short‐Term Caloric Restriction Induces Coordinated Changes That Promote Lipid Deposition While Maintaining Thermogenesis Capacity in Interscapular Brown Adipose Tissue of Male Rats

ABSTRACT Calorie restriction (CR) without malnutrition improves metabolic health, slows the aging process, and prolongs longevity. Brown adipose tissue (BAT), which specializes in burning energy to produce heat, also contributes to metabolic health; however, the effects of CR on BAT function are only partially understood, and even less is known about those exerted by mild CR for a short period of time. We studied the multifaceted relationship between mild short‐term CR (15% applied for 2 weeks) and intrascapular BAT (iBAT) in rats and provided insights into the adaptations occurring in the tissue through multiple complementary approaches: histology, mitochondrial respirometry, comprehensive quantitative proteomics, and targeted metabolomics. Our data indicate that mild short‐term CR induces structural and metabolic adaptations in iBAT aimed at the deposition of triglycerides within the adipocyte, which appear paucilocular. CR increases the levels of enzymes involved in glycolysis while simultaneously reducing glycolytic intermediate metabolites. It also improves the levels of enzymes involved in de novo lipogenesis, in providing reducing power for lipid synthesis, and in lipid droplet dynamics. Although CR reduced mitochondrial iBAT content, tissue thermogenic potential was maintained, as it increased mitochondrial activity, compensating for their lower abundance. Overall, our data indicate that mild CR, within 2 weeks, affects BAT metabolism, inducing physiological adaptation that preserves its thermogenic capacity under conditions of energy deficit. These adaptations may represent a key mechanism underlying the systemic benefits of CR, offering new insights into the role of even mild and short‐term CR in maintaining overall health.