Graphical abstract

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Background/Aim: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy. Method: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp. Results: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9—a GLP-1 receptor antagonist—worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates. Conclusions: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

The molecular clock machinery regulates several homeostatic rhythms, including glucose metabolism. We previously demonstrated that Roux-en Y Gastric Bypass (RYGB) has a weight-independent effect on glucose homeostasis, and transiently reduces food intake. In this study we investigate the effects of RYGB on diurnal eating behavior as well as its effects on the molecular clock, and its requirement for the metabolic effects of this bariatric procedure in obese mice. We find that RYGB reverses the high fat diet-induced disruption in diurnal eating pattern during the early post-surgery phase of food reduction. "Dark-cycle" pair-feeding experiments improved glucose tolerance to the level of bypass-operated animals during the physiologic "fasting" phase (Zeitgeber ZT2), but not the "feeding" phase (ZT14). Using a clock gene reporter mouse model (mPer2 Luc ), we reveal that RYGB induces a liver-specific phase shift in peripheral clock oscillation with no changes to the central clock activity within the suprachiasmatic nucleus (SCN). In addition, we show that weight loss effects are attenuated in obese Clock Δ19 mutant mice post-RYGB that also fail to improve glucose metabolism after surgery, specifically hepatic glucose production. We conclude that RYGB reprograms the peripheral clock within the liver early after surgery to alter diurnal eating behavior and regulate hepatic glucose flux.

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