Chronic stress inhibits weight gain and decreases beta-hydroxybutyrate levels and glucose tolerance in female BALB/c fed a high-fat ketogenic diet.

INTRODUCTION: Known for its neuroprotective properties, the ketogenic diet (KD) recently has been shown to prevent weight loss induced by chronic stress in rats, although the mechanisms remain to be elucidated. The obesity-resistant BALB/c mouse is susceptible to chronic stress-induced weight loss, providing a useful model to study the interactions between diet and stress. OBJECTIVE: This study aimed to evaluate the potential of a ketogenic diet to prevent chronic stress-induced weight loss in the obesity-resistant BALB/c mouse strain. METHOD: BALB/c mice of both sexes, were divided into groups: (1) standard chow, (2) KD, (3) standard chow + stress, and (4) KD + stress. The stress groups were subjected to a restraint stress protocol for 23 d, 4 h a day. Morphometric changes, glucose tolerance, plasmatic corticosterone levels, and circulating ketone bodies were evaluated. RESULTS: Levels of β-hydroxybutyrate increased in the KD group in both sexes. However, under stress, the increase in ketone bodies was lower in female mice. Compared with standard chow-fed groups, females on a KD gained significant body weight, an effect lost in females under stress, with decreasing fat tissue deposits. In male mice, although no changes in body weight were observed in the KD group, the mass of adipose tissue depots increased and remained unchanged under stress. Under chronic stress both standard chow and KD-fed mice lost weight. Under KD, female and male BALB/c mice exhibited decreased water and food intake, as well as reduced glucose tolerance, under resting and chronic stress conditions. CONCLUSIONS: There is an interplay between chronic stress and ketogenic metabolism in BALB/c mice. In female mice, chronic stress interferes with ketogenesis, lowering beta-hydroxybutyrate levels and preventing weight gain whereas the KD inhibits chronic stress-induced glucose tolerance, this in a sex-dependent manner.