Ob/ob Mice Fail to Lose Weight on an Alternate‐Day Fasting Diet, Yet Improve Glucose Control

Abstract

Alternate day fasting (ADF) has proven effective for weight loss in humans and rodents on a high‐fat diet. Mice with a homozygous mutation in the ob gene are obese, diabetic, and exhibit reduced body temperature (Tb) with variable torpor bouts in the fed state. We tested the hypotheses that an ADF protocol in genetically obese mice would result in (i) body weight (BW) loss, (ii) improved glucose control, and (iii) induction of torpor on fasted days. We evaluated the physiological effects of ADF in control and ob/ob mice for caloric intake, BW, Tb, and circulating glucose and insulin. Adult female ob/ob mice were implanted with temperature telemeters and randomly assigned to either 1) ad lib food availability (n=6) or 2) an ADF protocol, where the mice were fasted every other day, with ad lib feeding between fasts (n=11). Over 18 days of ADF, ob/ob mice consumed 258±11 kcal, approximately two‐thirds of that consumed by ob/ob mice on an ad lib diet (410±21 kcal). Despite this, ob/ob mice on the ADF diet lost only 0.7±0.2g of BW compared to the 3.9 ± 1.3g weight gain by ad lib ob/ob mice. ADF caused long and deep bouts of torpor in ob/ob mice such that the average and minimum 48‐hour Tb was 34.0±0.2 and 26.1±0.2°C, respectively, as compared to ad lib ob/ob mice (35.2±0.3; 31.1±0.9°C, respectively). Circulating glucose fell in the ADF mice, but only on fasting days (ad lib 307±57, ADF‐Fed 271±8, ADF‐Fast 132±17 mg/dl). The HOMA index, which evaluates insulin sensitivity using circulating glucose and insulin, improved significantly in the ob/ob ADF mice, but only on fasting days (ad lib 913±349, ADF‐Fed 1256±393, ADF‐Fast 288±146). These data demonstrate that weight loss is diminished, likely due to the deep bouts of torpor on fasted days, even though ADF significantly reduces food intake in ob/ob mice. Further, circulating glucose and the HOMA index fell in the ob/ob ADF mice on fasting days, suggesting improved glucose control in the face of minimal weight loss.Support or Funding InformationSupported by 1R15HL120072‐01A1 to SJS