International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B34. In vivo Modulation of HMGIC Reduces Obesity

A. Anand and K. Chada,
Dept. of Biochemistry, UMDNJ-RWJMS 675 Hoes Lane, Piscataway, NJ 08854

The HMGI family of proteins consists of three members, HMGIC, HMGI and HMGI(Y), and are architectural factors which function as an essential component in the enhancesome. HMGIC is predominantly expressed in proliferating, undifferentiated mesenchymal cells and not detected in adult tissues. Its function in mesenchymal proliferation and differentiation has been further substantiated by the demonstration that HMGIC is disrupted and misexpressed in a number of mesenchymal tumor cell types. The latter include fat cell tumors (lipomas) and intriguingly, the Hmgic-/- mouse mutant reveals a deficiency in fat tissue.

To examine its role in adipogenesis and obesity, we first investigated Hmgic expression in adipose tissue. As expected, expression was not detected in adipose tissue isolated from mice fed a standard diet but surprisingly, expression was observed in the fat tissue isolated from mice fed a high-fat diet. The latter results were also obtained with the adipose tissue isolated from two genetically induced obese mice and expression was not detected in any other tissue. Therefore, different obesity stimuli cause the detection of Hmgic in adipose tissue.

To extend the above correlative studies, mice disrupted at the Hmgic locus were utilized in our further investigations. Significantly, mice with either a partial or complete deficiency of Hmgic resisted diet-induced obesity. Disruption of the Hmgic gene caused a striking reduction in the obesity induced by leptin deficiency (Lepob/Lepob), in a gene dose-dependent manner.

We propose that the proliferative expansion of undifferentiated preadipocytes requires HMGIC expression which could be mediated by the regulation of its binding ability during the cell cycle. In wild-type fat tissue, HMGIC expression is undetectable since the preadipocyte population forms a minor component of the adipose tissue. Under obesity-inducing conditions, adipocyte number increases due to an expansion of the preadipocyte population and causes Hmgic expression to become readily detectable in the adipose tissue. In the absence of Hmgic, in vivo, preadipocyte proliferation is not as extensive as in the wild-type mouse and leads to a mouse with fewer mature adipocytes and hence, 8-fold less fat. Similarly, under obesity-inducing conditions, the expansion of the preadipocytes in the Hmgic-/- and Hmgic+/- mouse is severely retarded.

These results have now led to our present studies to elucidate the HMGIC genomic pathway in adipogenesis and obesity. Differential gene expression from wild-type, Lepob/Lepob and Hmgic-/-/Lepob/Lepob adipose tissue has identified a number of genes that are in the HMGIC dependent obesity pathway.

In summary, these studies implicate a critical role for HMGIC and its pathway in fat cell proliferation and differentiation and therefore the protein could be an adipose specific target for the treatment of obesity.

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