Mechanisms and Treatment Strategies of Insulin resistance in Human Models of Obesity and Altered Fat Distribution

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.
 
1.) Investigation of the role of TNF-alpha in mediating 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 are conducting 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. Critical indices of inflammation, including CRP, IL-6 and adiponectin will be assessed along with measure s of insulin sensitivity. Tissue expression and TNF-R2, and TNF-alpha binding and related gene regulation will be assessed in fat, in collaboration with Rex Ahima, to confirm that sequestration of TNF-alpha in the circulation is significant enough to prevent local tissue effects.

2.) Assessment of the role of mitochondrial function to mediate obesity in children. Among adults with normal glucose levels and first degree relatives with Type II DM, mitochondrial dysfunction has been shown and may be an early event contributing to insulin resistance. In contrast, little is known about these relationships among children with insulin resistance, and in particular if mitochondrial dysfunction is an important event linking insulin resistance to obesity among the growing population of children with obesity. Using P31 spectroscopy to assess phosphocreatine recovery after maximal voluntary contraction, we are assessing mitochondrial function in vivo, comparing obese children with and without insulin resistance, compared to lean, non insulin resistant children, controlling for Tanner stage, age and race. Preliminary results to date look very promising with a clear relationship between insulin resistance and mitochondrial function demonstrated for the fist time in obese children. Of note this appears to be independent of BMI, suggesting that obesity per se in not the only contributing factor to the development of mitochondrial dysfunction and insulin resistance in this population.

3.) 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. Collectively these strategies inform us of the complex mechanisms of the insulin resistance and the role of specific fat depots, including the role played by the beneficial subcutaneous fat depot in models of acquired lipodystrophy. These models will help to inform the treatment of metabolic abnormalities, including insulin resistance, in generalized obesity. 

References:

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