Gut microbes regulate hepatic nuclear receptor expression (821.7)

Abstract

Gut microbes profoundly affect host health and physiology, exemplified by the finding that germ free (GF) mice are resistant to diet‐induced obesity. However, mechanisms behind this phenomenon are incompletely understood. Preliminary microarray results revealed that nuclear receptors (NR), constitutive androstane receptor (CAR) and peroxisome proliferator‐activated receptor (PPAR)α, were induced in GF versus conventional (Conv) mice. Due to their role in energy and lipid metabolism, we hypothesized that elevated levels of CAR and PPARα protect GF mice from diet‐induced weight gain. To establish proof of principle, Conv and GF mice were fed a lowfat (LF) or highfat (HF) diet for 4 weeks. Body weight, serum lipid levels, and hepatic NR and target gene expression were measured. As expected, HF‐fed Conv mice gained more weight than LF‐fed mice, while GF mice remained resistant to weight gain. GF mice displayed lower levels of portal triglycerides (TG) and free fatty acids versus Conv mice, suggesting increased uptake by peripheral tissues. Additionally, the HF diet reduced portal TG levels, but to a lesser extent in GF mice. PPARα target genes, cytochrome p450 (cyp)4a10 and cluster of differentiation 36/fatty acid translocase CD36/FAT, as well as CAR and its target cyp2b10 were highly expressed in GF mice compared to Conv mice. Interestingly, the HF diet significantly induced CD36 and CAR expression compared to the LF diet in Conv, but not in GF mice. Collectively, these findings suggest a relationship between the gut microbiota and hepatic NR expression. However, further studies are needed to better elucidate these interactions, functional consequences, and the mechanisms through which they occur.Grant Funding Source: Supported by NIH 3T32DK007074‐39S1