Abstract
Browning of white adipose tissue (WAT) is currently considered a potential therapeutic strategy to treat diet-induced obesity. While some probiotics have protective effects against diet-induced obesity, the role of probiotics in adipose browning has not been explored. Here, we show that administration of the probiotic bacterium Lactobacillus amylovorus KU4 (LKU4) to mice fed a high-fat diet (HFD) enhanced mitochondrial levels and function, as well as the thermogenic gene program (increased Ucp1, PPARγ, and PGC-1α expression and decreased RIP140 expression), in subcutaneous inguinal WAT and also increased body temperature. Furthermore, LKU4 administration increased the interaction between PPARγ and PGC-1α through release of RIP140 to stimulate Ucp1 expression, thereby promoting browning of white adipocytes. In addition, lactate, the levels of which are elevated in plasma of HFD-fed mice following LKU4 administration, elicited the same effect on the interaction between PPARγ and PGC-1α in 3T3-L1 adipocytes, leading to a brown-like adipocyte phenotype that included enhanced Ucp1 expression, mitochondrial levels and function, and oxygen consumption rate. Together, these data reveal that LKU4 facilitates browning of white adipocytes through the PPARγ-PGC-1α transcriptional complex, at least in part by increasing lactate levels, leading to inhibition of diet-induced obesity.
Highlights
Browning of white adipose tissue (WAT) is currently considered a potential therapeutic strategy to treat diet-induced obesity
We demonstrate that administration of Lactobacillus amylovorus KU4 (LKU4), a probiotic bacterium, to mice fed a high-fat diet (HFD) increased mitochondrial levels and expression of brown adipose tissue (BAT)-selective genes in inguinal WAT (iWAT), with a concomitant increase in body temperature; we show that lactate mediates these effects of LKU4 on the browning of white adipocytes by remodeling the PPARγ transcription complex through switching RIP140 to PGC-1α, leading to protection against HFD-induced obesity
Mice fed a HFD with LKU4 oral supplementation (HFD-LKU4 mice) showed a reduction in body weight gain (19%), as well as in liver (34%), epididymal (47%), and inguinal WAT weight (48%), compared to mice fed a HFD (HFD mice) (Fig. 1A,C), even though food intake was comparable between the two groups (Fig. 1B)
Summary
Browning of white adipose tissue (WAT) is currently considered a potential therapeutic strategy to treat diet-induced obesity. In metabolic tissues, reducing adiposity and thereby protecting against diet-induced obesity and its related metabolic disorders[9,10,11,12] This suggests that this beneficial effect of probiotic bacteria may be associated with beige conversion of WAT; we hypothesized that some probiotics may promote or induce browning of white adipocytes, which, in turn, may facilitate energy expenditure and protect against diet-induced obesity. We demonstrate that administration of Lactobacillus amylovorus KU4 (LKU4), a probiotic bacterium, to mice fed a HFD increased mitochondrial levels and expression of BAT-selective genes in iWAT, with a concomitant increase in body temperature; we show that lactate mediates these effects of LKU4 on the browning of white adipocytes by remodeling the PPARγ transcription complex through switching RIP140 to PGC-1α, leading to protection against HFD-induced obesity
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