Summary Circadian disruption is associated with obesity, implicating the central clock in body weight control. Our comprehensive screen of wild-type and three circadian mutant mouse models, with or without chronic jet-lag, shows that distinct genetic and physiologic interventions differentially disrupt overall energy homeostasis and Leptin signaling. We found that BMAL1/CLOCK generates circadian rhythm of C/EBPα-mediated leptin transcription in adipose. Per- and Cry-mutant mice show similar disruption of peripheral clock and deregulation of leptin in fat, but opposite body weight and composition phenotypes that correlate with their distinct patterns of POMC neuron deregulation in the arcuate nucleus. Chronic jet-lag is sufficient to disrupt the endogenous adipose clock and also induce central Leptin resistance in wild-type mice. Thus, coupling of the central and peripheral clocks controls Leptin endocrine feedback homeostasis. We propose that Leptin resistance, a hallmark of obesity in humans, plays a key role in circadian dysfunction-induced obesity and metabolic syndromes.

NSAID use is limited due to the drugs’ toxicity to the gastrointestinal mucosa, an action incompletely understood. Lower gut injury induced by NSAIDs is dependent on bile secretion and is reported to increase the growth of a number of bacterial species, including an enterococcal species, Enterococcus faecalis. This study examined the relationships between indomethacin (INDO)‐induced intestinal injury/bleeding, small bowel overgrowth (SBO) and dissemination of enterococci, and the contribution of bile secretion to these pathological responses. Rats received either a sham operation (SO) or bile duct ligation (BDL) prior to administration of two daily subcutaneous doses of saline or INDO, and 24 h later, biopsies of ileum and liver were collected for plating on selective bacterial media. Fecal hemoglobin (Hb) and blood hematocrit (Hct) were measured to assess intestinal bleeding. Of the four treatment groups, only SO/INDO rats experienced a significant 10‐ to 30‐fold increase in fecal Hb and reduction in Hct, indicating that BDL attenuated INDO‐induced intestinal injury/bleeding. Ileal enterococcal colony‐forming units were significantly increased (500‐ to 1000‐fold) in SO/INDO rats. Of all groups, only the SO/INDO rats demonstrated gut injury, and this was associated with enterococcal overgrowth of the gut and dissemination to the liver. We also demonstrated that INDO‐induced intestinal injury and E. faecalis overgrowth was independent of the route of administration of the drug, as similar findings were observed in rats orally dosed with the NSAID. Bile secretion plays an important role in INDO‐induced gut injury and appears to support enterococcal overgrowth of the intestine. NSAID‐induced enterococcal SBO may be involved either as a compensatory response to gut injury or with the pathogenic process itself and the subsequent development of sepsis.

No abstract