Steven Grinspoon, MD

Institution: Massachusetts General Hospital
Research: Metabolic Regulation of Ectopic Adipose Tissue
Grants & Publications: Harvard Catalyst
Categories: MGH

Dr. Grinspoon is Chief of the Metabolism Unit and his research group focuses on understanding the metabolic consequences of abnormal fat distribution in lipodystrophy, and strategies to reduce ectopic adipose tissue and related inflammation. NAFLD is major consequence of dysfunctional adipose tissue and associated with insulin resistance and diabetes in lipodystrophy.

1) The group has shown reduced DICER in relationship to altered brown fat and metabolic regulation of adipose tissue and altered miRNA’a in this group. Of note the adipose DICER knockout demonstrated a lipodystrophic phenotype with severe insulin resistance, suggesting this pathway may be involved in regulating glucose regulation in lipodystrophy.

2) Dr. Grinspoon’s group has demonstrated reduced growth hormone pulsatility among lipodystrophic patients with excess visceral adipose tissue, strongly related to liver fat and has developed a novel hypothalamic peptide to augment endogenous GH pulsatility which was shown to reduce liver fat and visceral adiposity, while preventing liver fibrosis progression, in lipodystrophy, as well as selectively reducing VAT in generalized obesity. In Phase III trials for visceral adiposity, the therapy was associated with a 20% relative reduction in VAT vs. placebo and the larger the reduction in VAT, the lower the A1C, demonstrating the important relationship of this compartment to glucose control. Using banked tissue, the group has shown that IGF-I transcription is progressively reduced with advancing stages of liver disease, and is inversely related to glucose parameters, independent of circulating IGF-I, with implications for glucose control in NAFLD.

3) In a third set of studies, the group has shown that the renin angiotensin system is turned on in relationship to excess VAT ion lipodystrophy. Key studies investigating effects of RAAS blockade on this axis have shown reduced inflammatory proteins and reduced ectopic adipose tissue, but with a low BNP. Studies are ongoing to investigate effects of a dual strategy of blocking the RAAS with a neprilysin inhibitor to simultaneously augment BNP.