Metabolic dysfunction in lipodystrophy and obesity
This Program investigates critical question relating to the physiological regulation and clinical consequences of adipose tissue accumulation in models of obesity and acquired lipodystrophy. The research is aimed at elucidating the mechanisms and novel treatment strategies for insulin resistance in human models, including obesity and acquired lipodystrophy with visceral fat accumulation, subcutaneous fat loss and ectopic fat accumulation in the muscle, including strategies to improve mitochondrial function.
- Investigation of the role of TNF-alpha in mediating inflammation and insulin resistance in vivo. Activation of the TNF-alpha cascade has been posited as playing a central role in mediating insulin resistance in patients with obesity, and blockade of this axis has been shown to improve inflammation and insulin resistance in animal models. In humans with obesity and excess visceral fat, adipocyte-mediated secretion of TNF-alpha may be excessive and link excess fat accumulation to up-regulation of the inflammatory cascade and insulin resistance. To address his question, we conducted a novel, randomized, placebo controlled study among patients with obesity and insulin resistance, administering etanercept, a monoclonal antibody to TNF-alpha, to sequester TNF in the circulation and prevent it’s binding to receptors in local tissues.
- Improving mitochondrial function through inhibition of lipolysis in obesity. A critical mechanism of insulin resistance in obesity may relate to excess lipolysis and with excess ectopic fat in muscle and other critical depots. Acipimox is a lipolytic blocker which inhibits hormone sensitive lipase and reduces lipolysis a as well as triglyceride levels. Prior data by this group demonstrates effects of this strategy to improve insulin sensitivity and reduce ectopic fat accumulation in the muscle in a model of acquired lipodystrophy. As excess free fatty acids (FFA) may also contribute to decreased mitochondrial function, we will assess for the first time how this strategy to inhibit lipolysis with acipimox may improve mitochondrial function in association with insulin resistance. Using P31 spectroscopy to assess phosphocreatine recovery after sub-maximal exercise, we are assessing mitochondrial function in vivo, comparing those treated with acipimox vs. placebo as well as detailed indices of mitochondrial function.
- Investigation of the role of specific strategies to improve insulin resistance, through manipulation of critical fat depots in acquired lipodystrophy. Using HIV lipodystrophy as a model of acquired visceral fat accumulation and subcutaneous fat loss, we have investigated novel strategies to improve insulin resistance by increasing subcutaneous fat, using PPAR gamma agonists, selectively reducing visceral fat, by augmenting reduced endogenous GH pulsatility, and by reducing intramuscular lipid, by inhibiting lipolysis using acipimox, a nicotinic acid analogue. These unique strategies, each affecting a critical fat depot are likely to improve insulin resistance by different mechanisms and will shed light on the pathogenesis of insulin resistance and the optimal strategies for it’s treatment. Importantly, unlike current strategies which bluntly aim to reduce weight, these strategies target specific fat depots and may not induce weight loss, or may even increase weight, especially for PPAR gamma agonists, yet improve insulin resistance.
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Last Updated on September 29, 2020