Gut microbiota is involved in intermittent fasting-induced metabolic improvement in mice

Obesity and related metabolic disorders are reaching pandemic prevalence in Western countries. Although there is no single solution to the obesity epidemic because it is a complex problem that deserves a multifaceted approach, intermittent fasting has been suggested as an effective way to control weight. However, treatment studies in humans are yet inconclusive when compared to daily calorie restriction and mechanisms that explain its efficacy are poorly understood.

A new study, led by Dr. Frank J. Gonzalez from the Laboratory of Metabolism at the Centre for Cancer Research, National Cancer Institute, at the National Institutes of Health (Bethesda, USA), has found that gut microbiota mediates the effects of intermittent fasting on activation of beige thermogenesis and subsequently metabolic improvements in mice.

Conversion of white adipose tissue (WAT) to beige fat has been suggested as a promising target for therapy for obesity and related metabolic diseases, although its clinical potential is not yet clear. In this study, mice were placed on an every-other-day fasting (EODF) regimen in order to explore its effect on white adipose tissue beiging and metabolic disorders. The EODF group was fed in alternating 24-hour periods (15 cycles for long-term study and 3 cycles for short-term study) of free access to food followed by 24 hours of fasting, while the ad libitum (AL) group was allowed unrestricted access to food.

When compared with the AL group, the 15-cycle EODF group increased energy expenditure through favouring fat burning rather than utilization of carbohydrates. Besides this, EODF selectively induced beige fat development of subcutaneous (inguinal) WAT and ameliorated obesity, insulin resistance, and hepatic steatosis. EODF-induced WAT beiging was independent of signalling by b-adrenergic receptor and fibroblast growth factor-21 – a classical signalling hormone involved in regulating WAT browning- and the peroxisome proliferator-activated receptor (PPAR)-alpha -which plays an essential role in energy metabolism.

As previous research has found that the gut microbial communities can be involved in the regulation of brown and beige adipose tissues and fasting and feeding rhythms can also alter the gut microbiota, the researchers then explored whether the gut microbiota could take part in mediating EODF-induced WAT beiging.

EODF treatment led to a shift in the gut microbiota composition and increased the levels of the short-chain fatty acids acetate and lactate. Although Firmicutes and Bacteoidetes were the most abundant phyla in AL mice, EODF led to an increase of the phyla operational taxonomic unit of Firmicutes while decreasing most other phyla. A similar shift in the gut microbiota composition was reported to be related to increased glucose uptake in inguinal WAT, which is consistent with current results of this study. Looking deeper into the mechanism of action involved, gut microbiota orchestrated EODF-induced WAT beiging involved a selective upregulation of monocarboxylate transporter 1 (Mct1) expression in beige cells, which drives acetate and lactate transport across the plasma membrane of adipocytes.

In order to investigate whether the EODF-induced microbial shift directly contributed to WAT beiging, the gut microbiota from both EODF and AL mice were transplanted to microbiota-depleted mice. Microbiota-depleted mice were resistant to EODF-induced beiging as the induction of Mct1 and changes in serum acetate and lactate were suppressed. Besides this, transferring the gut microbiota from EODF-treated mice to microbiota-depleted mice activated beiging and improved metabolic homeostasis. Thus, microbial metabolites acetate and lactate underlie the mechanism of EODF-induced WAT beiging. Taken together, these data show that EODF primarily alters the gut microbiota composition to promote the generation of acetate and lactate and, as a result, to activate WAT beiging.

On the whole, these results suggest that an intermittent fasting (every-other-day fasting) regimen can selectively induce the beiging of white adipose tissue and subsequently improve metabolic disorders in mice. In this process, the gut microbiota is one of the mechanisms behind EODF-induced metabolic improvement.

Reference:

Li G, Xie C, Lu S, et al. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab. 2017; 26(4):672-85. doi: 10.1016/j.cmet.2017.08.019.