Abstract 10267: Thermogenic Modulation of Perivascular Adipose Tissue Ameliorates Cardioautonomic Deterioration in Prediabetes

Abstract

Introduction: Cardiac autonomic neuropathy, a risk factor of cardiovascular mortality, is a common manifestation of prediabetes. Evidence points to perivascular adipose tissue inflammation as a quintessential instigator of cardiovascular dysfunction in metabolic impairment. Interventions tailored to ameliorate such subtle cardiovascular involvement have not been forthcoming. Data emerging from our laboratory implicate alteration of adipocyte mitochondrial bioenergetics, particularly an upregulation of uncoupling protein 1 (UCP1) expression and subsequent augmentation of adipose tissue hypoxia, as a potential culprit driving localized adipose inflammation. Hypothesis: Inhibition of UCP1-mediated thermogenesis or activation of the alternative thermogenic pathway, futile creatine cycling, through supplementation with phosphate or creatine monohydrate, respectively, may ameliorate the inflammatory phenotype observed in non-obese prediabetic rats. Methods: A non-obese prediabetic rat model, developed in our laboratory was used. This phenotype is evoked by 12 weeks of hypercaloric feeding causing localized perivascular inflammation in absence of systemic markers of inflammation. Cardioautonomic function was assessed by invasive hemodynamics. Localized adipose tissue inflammation and macrophage polarization were examined. Results: UCP1 inhibition by phosphate supplementation reversed the blunted parasympathetic baroreflex sensitivity observed in prediabetic rats. This was associated with the alleviation of perivascular adipose tissue hypoxia, inflammation, and altered macrophage polarization. These changes were accompanied by normalization of metabolic efficiency that increased in prediabetic rats due to UCP1 upregulation. Similar functional effects were observed after creatine supplementation without changes in metabolic efficiency. Conclusions: Bypassing UCP1-mediated thermogenesis upregulated by increased caloric intake alleviates cardioautonomic deterioration triggered by perivascular inflammation. This is achieved by UCP1 inhibition with a potential risk of increased metabolic efficiency and weight gain, or by activation of the alternative thermogenic pathway of creatine cycling.