Alternate-day feeding leads to improved glucose regulation on fasting days without significant weight loss in genetically obese mice

Abstract

Alternate-day fasting (ADF) is effective for weight loss and increases insulin sensitivity in diet-induced obese rodents. However, the efficacy of ADF in genetic models of obesity has not been comprehensively studied. Mice that are deficient in leptin ( ob/ob mice) are obese, diabetic, and prone to deep bouts of torpor when fasted. We tested the hypotheses that an ADF protocol in ob/ob mice would result in 1) induction of torpor on fasted days, 2) minimal body weight loss if the mice experienced torpor, and 3) no improvement in glucose control in the absence of weight loss. Female ob/ob mice and littermate controls were assigned to 1) an ad libitum regimen or 2) an ADF regimen, consisting of fasting every other day with ad libitum feeding between fasts. Over a 19-day period, littermate control mice on the ADF regimen consumed the same amount of food as littermate control mice on the ad libitum regimen, whereas the ADF ob/ob mice consumed 37% less food than ad libitum ob/ob mice. Fasting days, but not fed days, led to torpor in both genotypes. Fasting days, but not fed days, led to weight loss in both genotypes relative to ad libitum controls. Fasting days, but not fed days, produced enhanced insulin sensitivity in both genotypes and normalized circulating glucose in ob/ob mice. These data demonstrate improved glucose control on fasting days with the use of ADF in a genetic model of obesity in the face of minimal weight loss.

Health Effects of Alternate Day Fasting Versus Pair-Fed Caloric Restriction in Diet-Induced Obese C57Bl/6J Male Mice

“…diet groups showed a decreased fasting blood glucose relative to HF mice, as seen previously, with the ADF group exhibiting lower blood glucose despite the measurement taken after a fed day (Anson et al, 2003;Gotthardt et al, 2016;Yang et al, 2016;Liu et al, 2018). The improved glucose control seen in ADF mice compared to ad libitum controls is well known in rodents and humans (Joslin et al, 2017;Dedual et al, 2019;Swoap et al, 2019). We found that all of the diet manipulations lead to improved GTT responses relative to the HF group, confirming those findings.…”

“…Alternate day fasting (ADF) is a form of intermittent fasting defined by alternating days of fasting (with full access to water and other calorie-free beverages) and ad libitum eating. ADF is an effective form of intermittent fasting that leads to weight loss, specifically fat mass (Varady et al, 2011;Baumeier et al, 2015;Catenacci et al, 2016;Joslin et al, 2017;Trepanowski et al, 2017;Gabel et al, 2019;Parvaresh et al, 2019), improved glucose control and insulin sensitivity (Halberg et al, 2005;Heilbronn et al, 2005;Yang et al, 2016;Swoap et al, 2019), and lowered circulating lipids and cholesterol in both rodents and humans (Mahoney et al, 2006;Bhutani et al, 2013;Varady et al, 2015). In rodent models, ADF has also been shown to increase cancer survival (Descamps et al, 2005;Varady et al, 2009;Xie et al, 2017), increase mean and maximal life span (Anson et al, 2003;Descamps et al, 2005), and reduce the effects of specific diseases such as asthma (Johnson et al, 2007).…”

“…We have previously shown that obese high-fat fed male C57Bl/6J mice have significant health gains (in terms of body weight (BW) and glucose regulation) when they undergo ADF while continuing on the high-fat diet (Joslin et al, 2017). Given the prevalent association of glucose dysregulation with obesity, many measures of glucose regulation [e.g., fasting blood levels, glucose tolerance tests, insulin-assisted glucose tolerance tests (IAGTs)] are used to assess the efficacy of ADF and CR (Varady et al, 2010;Baumeier et al, 2015;Hatting et al, 2017;Smith et al, 2019;Swoap et al, 2019). Plasma corticosterone and IL6, markers of stress and inflammation, respectively, have been shown to increase with a high-fat diet (Emerson et al, 2017;Appiakannan et al, 2019).…”

Intermittent Fasting: Potential Bridge of Obesity and Diabetes to Health?

“…Nevertheless, it is worth noting that isocaloric IF may not be an effective approach for regulating body weight in genetical obesity when compared to diet-induced obesity. Minimum weight loss was observed on genetically obese mice and wild-type (control) mice after 18 days of ADF, consisting of ad libitum chow availability for 24 h followed by complete fasting for the next 24 h [ 36 ]. For wild-type mice, however, this ADF protocol did not appear to influence total food intake either, as the mice on the ADF regimen consumed double the amount of food of control mice on the ad libitum regimen on feeding days, potentially resulting in the absence of weight loss with the ADF protocol.…”

Fasting: How to Guide

“…In obese mice, the ADF regimen with an HF diet results in weight loss, improved blood glucose control and daily fluctuations in selected physiological and biochemical parameters [ 82 ]. Glucose control is improved on fasting days with the use of ADF in a genetic model of obesity in the face of minimal weight loss [ 83 ]. ADF could significantly inhibit Type 2 Diabetes (T2D) induced insulin resistance and obesity, promote insulin signaling, reduce inflammation, and promote glycogen synthesis and lipid metabolism.…”