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. 2019 Feb 21;9(1):2479.
doi: 10.1038/s41598-019-39380-2.

Thermogenesis-independent metabolic benefits conferred by isocaloric intermittent fasting in ob/ob mice

Yun Hye Kim  1 , Ju Hee Lee  1   2 , Joanna Lan-Hing Yeung  1 , Eashita Das  1   3 , Ri Youn Kim  4   5 , Yanqing Jiang  1 , Joon Ho Moon  1 , Hyerin Jeong  1 , Nikita Thakkar  1 , Joe Eun Son  6 , Natasha Trzaskalski  4   7 , Chi-Chung Hui  6   8 , Kyung-Oh Doh  9 , Erin E Mulvihill  4   7 , Jae-Ryong Kim  10 , Kyoung-Han Kim  11   12 , Hoon-Ki Sung  13   14   15
Affiliations

Thermogenesis-independent metabolic benefits conferred by isocaloric intermittent fasting in ob/ob mice

Yun Hye Kim et al. Sci Rep. .

Abstract

Intermittent fasting (IF) is an effective dietary intervention to counteract obesity-associated metabolic abnormalities. Previously, we and others have highlighted white adipose tissue (WAT) browning as the main underlying mechanism of IF-mediated metabolic benefits. However, whether IF retains its efficacy in different models, such as genetically obese/diabetic animals, is unknown. Here, leptin-deficient ob/ob mice were subjected to 16 weeks of isocaloric IF, and comprehensive metabolic phenotyping was conducted to assess the metabolic effects of IF. Unlike our previous study, isocaloric IF-subjected ob/ob animals failed to exhibit reduced body weight gain, lower fat mass, or decreased liver lipid accumulation. Moreover, isocaloric IF did not result in increased thermogenesis nor induce WAT browning in ob/ob mice. These findings indicate that isocaloric IF may not be an effective approach for regulating body weight in ob/ob animals, posing the possible limitations of IF to treat obesity. However, despite the lack of improvement in insulin sensitivity, isocaloric IF-subjected ob/ob animals displayed improved glucose tolerance as well as higher postprandial insulin level, with elevated incretin expression, suggesting that isocaloric IF is effective in improving nutrient-stimulated insulin secretion. Together, this study uncovers the insulinotropic effect of isocaloric IF, independent of adipose thermogenesis, which is potentially complementary for the treatment of type 2 diabetes.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Isocaloric intermittent fasting does not modify body weight in ob/ob mice. (A) An experiment scheme of the 2:1 intermittent fasting (IF) regimen. (B) Daily energy intake during 16 weeks of IF cycles. (C) Total energy intake during 16 weeks of IF cycles. (D) Body weight measurement of ob/ob mice for 16 weeks. (E) Body composition of fat and lean mass in ob/ob mice subjected to the ad libitum (Ob-AL), ob/ob mice subjected to the pair-fed ad libitum (Ob-PF) and ob/ob mice subjected to the intermittent fasting (Ob-IF). Data are expressed as mean ± s.e.m. (Ob-AL: n = 4; Ob-PF: n = 7; Ob-IF: n = 6); Ob-AL vs. Ob-PF: $P < 0.05; Ob-AL vs. Ob-IF: #P < 0.05; Ob-PF vs. Ob-IF: *P < 0.05.
Figure 2
Figure 2
Isocaloric intermittent fasting does not reduce fat mass nor improve fatty liver phenotype in ob/ob mice. (A) Tissue weights of inguinal and perigonadal white adipose tissue (IWAT and PWAT, respectively), brown adipose tissue (BAT), and liver. (B) H&E stained sections of IWAT, PWAT, BAT and liver. (C) Liver triglyceride level. Data are expressed as mean ± s.e.m. (Ob-PF: n = 6–7; Ob-IF: n = 5–6).
Figure 3
Figure 3
Isocaloric intermittent fasting partially improves glucose homeostasis in ob/ob mice. (A) Glucose tolerance test (GTT) in Ob-PF (n = 12) and Ob-IF (n = 11) mice. (B) Quantification of the area under the curve (AUC) from the IPGTT. (C) Insulin tolerance test (ITT). (D) Quantification of AUC from the IPITT. Data are expressed as mean ± s.e.m. (Ob-PF: n = 6–7; Ob-IF: n = 5–6); Ob-PF vs. Ob-IF: *P < 0.05.
Figure 4
Figure 4
Isocaloric intermittent fasting does not stimulate adipose thermogenesis  in ob/ob mice. (A) The change of O2 consumption normalized by body weight and (B) average of O2 consumption per hour during fasting and feeding periods, and combined. (C) The change of activity and (D) average of physical activities per hour during fasting and feeding periods, and combined. No changes in browning marker gene expression in (E) PWAT, (F) IWAT, and (G) BAT of Ob-IF. Data are expressed as mean ± s.e.m. (Ob-PF: n = 7; Ob-IF: n = 6); Ob-PF vs. Ob-IF: *P < 0.05.
Figure 5
Figure 5
Isocaloric intermittent fasting does not modify expression levels of adipose-derived factor and inflammatory genes in ob/ob mice. (A) No changes in Vegfa mRNA expression in PWAT, IWAT, and BAT. mRNA expression levels of Cfd, Adipoq, and Nrg4 in (B) PWAT, (C) IWAT, and (D) BAT. Inflammatory marker gene expression analysis in (E) PWAT and (F) IWAT. Data are expressed a mean ± s.e.m. (Ob-PF: n = 7; Ob-IF: n = 6); Ob-PF vs. Ob-IF: *P < 0.05.
Figure 6
Figure 6
Isocaloric intermittent fasting enhances insulin and incretin production in ob/ob mice. (A) Homeostatic model assessment of insulin resistance (HOMA-IR). (B) The plasma insulin levels of Ob-PF and Ob-IF in fasting and postprandial conditions. (C) Glucose-stimulated insulin secretion measured before and 30 min after glucose i.p. injection. (D,E) The total plasma GLP-1 and GIP levels of Ob-PF and Ob-IF mice in fasting condition. Data are expressed as mean ± s.e.m. (Ob-PF: n = 7; Ob-IF: n = 6); Ob-PF vs. Ob-IF: *P < 0.05.
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