Steven Grinspoon, M.D.

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.

  1. 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.

  2. 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.

  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.

References
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1. Bernstein LE, Berry J, Kim S, Canavan B, Grinspoon SK. Effects of Etanercept in the Metabolic Syndrome. Arch Int Med. 2006; 166: 902 - 908.

2. Hadigan C, Liebau J, Torriani M, Andersen R, Grinspoon S.  Improved Triglycerides and Insulin Sensitivity with 3 Months of Acipimox in HIV-infected Patients with Hypertriglyceridemia. J Clin Endocrinol Metab. 2006;91:4438-44.

3. McCormack S, McCarthy M, Farilla L, Hrovat M, Systrom D, Grinspoon S, Fleischman A. Skeletal Muscle Mitochondrial Function is Associated with Longitudinal Growth Velocity in Children and Adolescents. J Clin Endocrinol Metab. 2011 Oct;96(10):E1612-8. PMCID: PMC3200245

4. Zanni M*, Burdo T*, Makimura H, Williams K, Grinspoon S. Relationship between Monocyte/Macrophage Activation Marker in Soluble CD163 and Insulin Resistance in Obese and Normal-Weight Subjects. Clin Endocrinol (Oxf). 2012 Sep; 77(3):385-90 PMCID:PMC3660104

5. Fitch K, Abbara S, Lee H, Stavrou E, Sacks R, Michel T, Hemphill L, Torriani M, Grinspoon S.Effects of Lifestyle Modification and Metformin on Atherosclerotic Indices among HIV-Infected Patients with the Metabolic Syndrome. AIDS. 2012 Mar 13;26(5):587-97. PMCID:PMC3675446

6. Torriani M, Fitch K, Stavrou E, Bredella M, Lim R, Sass C, Cypess A, Grinspoon S. Deiodinase 2 Expression is Increased in Dorsocervical Fat of Patients with HIV-Associated Lipohypetrophy Syndrome. J Clin Endocrinol Metab. 2012 Apr;97(4):E602-7 PMCID:PMC3319185

7. Stanley TL, Falutz J, Marsolais C, Morin J, Soulban G, Mamputu JC, Assad H, Turner RR, Grinspoon SK. Reduction in Visceral Adiposity is Associated with Improved Metabolic Profile in HIV-infected Patients Receiving Tesamorelin. Clin Inf Dis. 2012 Jun;54(11):1642-51. PMCID:PMC3348954

8. McCormack S, Shaham O, McCarthy M, Deik A, Wang T, Gerszten R, Clish C, Mootha V, Grinspoon SK, Fleischman A. Circulating Branched-chain Amino Acid Concentrations Are Associated with Obesity and Future Insulin Resistance in Children and Adolescents. Pediatric Obesity 2013 Feb;8(1):52-61 PMCID:PMC3519972

9. McCormack S, McCarthy M, Harrington S, Farilla L, Hrovat M, Systrom D, Thomas B, Torriani M, McInnis K, Grinspoon S, Fleischman A. Effects of Exercise and Lifestyle Modification on Fitness, Insulin Resistance, Skeletal Muscle Oxidative Phosphorylation, and Intramyocellular Lipid Content in Obese Children and Adolescents. Pediatr Obes. 2013 Jun 25. [Epub ahead of print] PMCID:PMC3808470

10. Makimura H, Murphy CA, Feldpausch MN, Grinspoon SK. The Effects of Tesamorelin on Phophocreatine Recovery in Obese Subjects with Reduced GH. J Clin Endocrinol Metab. 2014 Jan;99(1):338-43. PMCID:PMC3879673

 

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