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Metabolic syndrome (MetS) is as a cluster of cardio-metabolic factors that greatly increase the risk of chronic diseases such as type II diabetes mellitus and atherosclerotic cardiovascular disease. In the United States, obesity, physical inactivity, aging, and genetics (to a minor extent) have arisen as risk factors for developing MetS. Although 35% of American adults suffer from MetS, its pathogenesis largely remains unknown. Worse, there is a lack of screening and optimum therapy for this disease. Researchers have consequently turned towards metabolomics to identify biomarkers to better understand MetS. The purpose of this review is to characterize various metabolites and their potential connections to MetS. Numerous studies have also characterized MetS as a disease of increased inflammation, and therefore this review also explores how metabolites play a role in various inflammatory pathways. Our review explores a broad range of metabolites including biogenic amines, branched chain amino acids, aromatic amines, phosphatidylcholines, as well as a variety of other molecules. We will explore their biochemical pathways and their potential role in serving as biomarkers.

BackgroundLow testosterone and obesity are independent risk factors for dysfunction of the nervous system including neurodegenerative disorders such as Alzheimer’s disease (AD). In this study, we investigate the independent and cooperative interactions of testosterone and diet-induced obesity on metabolic, inflammatory, and neural health indices in the central and peripheral nervous systems.MethodsMale C57B6/J mice were maintained on normal or high-fat diet under varying testosterone conditions for a four-month treatment period, after which metabolic indices were measured and RNA isolated from cerebral cortex and sciatic nerve. Cortices were used to generate mixed glial cultures, upon which embryonic cerebrocortical neurons were co-cultured for assessment of neuron survival and neurite outgrowth. Peripheral nerve damage was determined using paw-withdrawal assay, myelin sheath protein expression levels, and Na+,K+-ATPase activity levels.ResultsOur results demonstrate that detrimental effects on both metabolic (blood glucose, insulin sensitivity) and proinflammatory (cytokine expression) responses caused by diet-induced obesity are exacerbated by testosterone depletion. Mixed glial cultures generated from obese mice retain elevated cytokine expression, although low testosterone effects do not persist ex vivo. Primary neurons co-cultured with glial cultures generated from high-fat fed animals exhibit reduced survival and poorer neurite outgrowth. In addition, low testosterone and diet-induced obesity combine to increase inflammation and evidence of nerve damage in the peripheral nervous system.ConclusionsTestosterone and diet-induced obesity independently and cooperatively regulate neuroinflammation in central and peripheral nervous systems, which may contribute to observed impairments in neural health. Together, our findings suggest that low testosterone and obesity are interactive regulators of neuroinflammation that, in combination with adipose-derived inflammatory pathways and other factors, increase the risk of downstream disorders including type 2 diabetes and Alzheimer’s disease.

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