Absence of neurotensin attenuates intestinal dysbiosis and inflammation by maintaining Mmp7/α‐defensin axis in diet‐induced obese mice

Abstract

We previously reported that high levels of plasma neurotensin (NT), a gut hormone released from enteroendocrine cells of the small bowel, contribute to obesity and comorbid conditions. Gut microbiota has been implicated in the obesity development. Paneth cells are critical in maintaining gut microbiota composition and homeostasis by releasing antimicrobial proteins including α‐defensins. The purpose of our current study was to determine the possible role of NT in gut microbiota composition and α‐defensin gene expression associated with obesity. Here we show that the ratio of Firmicutes/Bacteroidetes (F/B ratio) and intestinal proinflammatory cytokines is significantly increased in NT+/+ mice fed with a high‐fat diet (HFD) which were improved in NT‐deficient mice. HFD disrupted the intestinal Mmp7/α‐defensin axis, which was completely prevented in NT−/− mice. In addition, NT treatment inhibited DEFA5 expression and concurrent NF‐κB activity, which was blocked by a pan PKC inhibitor (Gö6983) or an inhibitor for atypical PKCs (CRT0066854). More importantly, the shRNA‐mediated knockdown of atypical PKCτ reversed NT‐attenuated DEFA5 expression and increased NF‐κB activity. NT contributes to the HFD‐induced disruption of gut microbiota composition and α‐defensin expression. PKCτ/λ plays a central role in NT‐mediated α‐defensin gene expression which might be mediated through the inhibition of NF‐κB signaling pathways in Paneth cells.

The Role of Central Neurotensin in Regulating Feeding and Body Weight

“…However, ingesting dietary fat causes a rapid, transient elevation of Nts in the plasma ( 15 , 16 ), likely released from enteroendocrine cells ( 17 ). Nts promotes intraluminal fat absorption, which may explain why whole-body Nts knockout mice have reduced lipid uptake and are protected from developing diet-induced obesity ( 9 , 18 ). The peripheral Nts system seems directly coordinated with energy status, so that plasma Nts rapidly increases after ingestion ( 19 , 20 ), usually returning to basal levels hours later.…”

Neurotensin differentially regulates bile acid metabolism and intestinal FXR‐bile acid transporter axis in response to nutrient abundance

“…To determine whether NT affects BA metabolism, we quantified plasma BA composition at an early stage (ie, 6 weeks) and at a later stage (ie, 28 weeks) of obesity. We have shown that HFD consumption significantly increased body weight and fat mass in NT +/+ but not NT −/− mice at both early and later stages of obesity in our previous reports 10,23 . The plasma BA profiles of mice fed HFD for 6 weeks are summarized in Table 1 (glycine‐conjugated BAs were detected at noise levels and thus excluded).…”

“…For the induction of obesity, male mice were fed a 60% HFD or as a control, 10% low‐fat diet (LFD) (catalog no. D12492 and D12450B, respectively; Research Diets, New Brunswick, NJ) at weaning for 5‐6 or 26‐28 weeks, as described in our previous studies 10,23 . Mice were housed in standard cages in temperature‐controlled environments under a 12/12 hours light‐dark cycle with ad libitum access to food and water.…”

“…D12492 and D12450B, respectively; Research Diets, New Brunswick, NJ) at weaning for 5-6 or 26-28 weeks, as described in our previous studies. 10,23 Mice were housed in standard cages in temperature-controlled environments under a 12/12 hours light-dark cycle with ad libitum access to food and water. Prior to sacrifice, feces were collected from individually caged mice and stored at −80°C.…”

“…We have shown that HFD consumption significantly increased body weight and fat mass in NT +/+ but not NT −/− mice at both early and later stages of obesity in our previous reports. 10,23 The plasma BA profiles of mice fed HFD for 6 weeks are summarized in Table 1 (glycine-conjugated BAs were detected at noise levels and thus excluded). Taurine-conjugated forms of primary BAs including T-CA, T-UDCA, and T-β-MCA were found the dominant species in LFD-fed NT +/+ mice (Table 1).…”