Metabolic syndrome in TLR5 deficient mice is associated with microbiota dependent MUFA enriched hepatic lipids (133.6)

Abstract

Obesity (leptin deficiency) is associated with elevated monounsaturated fatty acids (MUFA) specifically palmitoleate (C16:1) and oleate (C18:1) in tissue neutral lipids. Toll Like Receptor 5 (TLR5), an innate immune receptor for bacterial flagellin is required for gut microbiota homeostasis. Accordingly, mice lacking TLR5 (TLR5KO) develop spontaneous low‐grade gut inflammation and metabolic syndrome, which are microbiota dependent. Here, we examined whether metabolic syndrome in TLR5KO mice is associated with elevated MUFA levels. We analyzed fatty acid composition of total lipid (TL), triglycerides (TG), cholesterol esters (CE) and phospholipid (PL) fractions of the tissue lipids in age and gender matched TLR5KO and their WT littermates. We also analyzed MUFA levels in high‐fat fed, TLR2 or 4 deficient TLR5KO, calorie restricted, microbiota ablated, germ‐free (GF) and conventionalized GF‐WT mice transplanted with either WT or TLR5KO microbiota. TLR5KO mice displayed elevated hepatic TG and CE and substantially elevated C18:1 in TL, TG and CE but not in PL when compared to WT mice. Interestingly, in TLR5KO mice C16:1 levels were comparable to WT mice. Such elevated C18:1 was restricted to hepatic lipids and not in serum and adipose tissue lipids. The elevated C18:1 was also observed in high fat fed and calorie restricted TLR5KO mice. In addition, deletion of TLR2/4 did not prevent accumulation of C18:1 in TLR5KO mice hepatic lipids. However, in microbiota‐ablated (via antibiotics) as well as GF TLR5KO mice, C18:1 levels were comparable to WT mice. Finally, the pronounced C18:1 accumulation in hepatic lipids was recapitulated in GF‐WT mice transplanted with microbiota from TLR5KO mice than WT microbiota recipients. Collectively, these data demonstrate that gut microbiota dysbiosis in TLR5KO mice drives hepatic lipogenesis probably via generating precursors for MUFA (short chain fatty acids) that may result in hepatic insulin resistance finally culminating into metabolic syndrome.Grant Funding Source: NIH K01 and R03