Microbiota-Produced N-Formyl Peptide fMLF Promotes Obesity-Induced Glucose Intolerance.
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ABSTRACT:
SUBMITTER: Wollam J
PROVIDER: S-EPMC6609982 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
Publications
Microbiota-Produced <i>N</i>-Formyl Peptide fMLF Promotes Obesity-Induced Glucose Intolerance.
Wollam Joshua J Riopel Matthew M Xu Yong-Jiang YJ Johnson Andrew M F AMF Ofrecio Jachelle M JM Ying Wei W El Ouarrat Dalila D Chan Luisa S LS Han Andrew W AW Mahmood Nadir A NA Ryan Caitlin N CN Lee Yun Sok YS Watrous Jeramie D JD Chordia Mahendra D MD Pan Dongfeng D Jain Mohit M Olefsky Jerrold M JM
Diabetes 20190422 7
The composition of the gastrointestinal microbiota and associated metabolites changes dramatically with diet and the development of obesity. Although many correlations have been described, specific mechanistic links between these changes and glucose homeostasis remain to be defined. Here we show that blood and intestinal levels of the microbiota-produced <i>N-</i>formyl peptide, formyl-methionyl-leucyl-phenylalanine, are elevated in high-fat diet-induced obese mice. Genetic or pharmacological in ...[more]
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Project description:Background Breakthroughs in HIV treatment, especially antiretroviral therapy (ART), have massively reduced mortality. However, ART-treated individuals display elevated rates of obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. These co-morbidities represent a considerable threat to long-term survival and quality of life. Previous studies have shown that high-fat feeding induces persistent low-grade systemic and adipose tissue inflammation contributing to insulin resistance and metabolic dysregulation via adipose-infiltrating macrophages. Methods and Results Studies herein test the hypothesis that ART potentiates the inflammatory effects of a high-fat diet (HFD). C57Bl/6J mice on a HFD or standard chow containing ART or vehicle, were subjected to functional metabolic testing, RNA-sequencing of epididymal white adipose tissue (eWAT), and array-based kinomic analysis of eWAT-infiltrating macrophages. ART-treated mice on a HFD displayed fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance. Gene set enrichment and kinomic array analyses revealed a pro-inflammatory transcriptional signature depicting granulocyte migration and activation. Conclusions The current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways in eWAT consistent with macrophage infiltration, resulting in impaired glucose metabolism, energy balance, and metabolic dysfunction.
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Project description:AimsGlucagon-like peptide 1 receptor agonists and dual agonists have changed the treatment landscape of obesity and type 2 diabetes (T2D), but significant limitations have emerged due to their gastrointestinal side effects, loss of lean mass, and necessity for ongoing subcutaneous injections. Our objective was, therefore, to test a novel small molecule as a different and potentially better tolerated oral medications to improve obesity-associated impairment in glucose homeostasis.Materials and methodsHigh-fat diet (HFD)-fed mice or severely obese, leptin-deficient ob/ob mice were randomly assigned to serve as controls or receive oral TIX100, a novel thioredoxin-interacting protein (TXNIP) inhibitor just approved by the FDA as an investigational new drug for type 1 diabetes (T1D). The TIX100 effects on glucose intolerance and weight control were then assessed.ResultsTIX100 protected against HFD-induced glucose intolerance, hyperinsulinemia, and hyperglucagonemia. TIX100 also reduced diet-induced adiposity resulting in 15% lower weight in treated mice as compared with controls on HFD (p <0.05), while preserving lean mass. Even though the TIX100 weight effects were lost in ob/ob mice, TIX100 improved glucose control leading to a dramatic 2.3% reduction in HbA1C (p <0.05), independent of any weight loss. This is consistent with the beneficial effects of TIX100 in non-obese diabetes models and its protection against elevated TXNIP and islet cell stress common to all diabetes types.ConclusionsThus, TIX100 may provide a novel, oral therapy for T2D that targets underlying disease pathology including islet cell dysfunction and hyperglucagonemia and promotes metabolic health and weight control without aggressive weight loss.
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Project description:BackgroundThe cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and β-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of β-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in β-cells.MethodsMice with a floxed GC-A gene were bred to Rip-CreTG mice, thereby deleting GC-A selectively in β-cells (β GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. β-cell size and number were measured by immunofluorescence-based islet morphometry.ResultsIn vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from β GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in β GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in β-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and β-cell morphology were similar in β GC-A KO mice and control littermates. However, HFD-fed β GC-A KO animals had accelerated glucose intolerance and diminished adaptative β-cell proliferation.ConclusionsOur studies of β GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate β-cell's growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of β-cells to HFD-induced obesity. Impaired β-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes.
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