In vivo modulation of Hmgic reduces obesity

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In vivo modulation of Hmgic reduces obesity


Ashim Anand & Kiran Chada The HMGI family of proteins consists of three members1,2, HMGIC, HMGI and HMGI(Y), that function as architectural factors3–5 and are essential components of the enhancesome6,7. HMGIC is predominantly expressed in proliferating, undifferentiated mesenchymal cells and is not detected in adult tissues8,9. It is disrupted and misexpressed in a number of mesenchymal tumour cell types10–12, including fat-cell tumours12 (lipomas). In addition Hmgic–/– mice have a deficiency in fat tissue13. To study its role in adipogenesis and obesity, we examined Hmgic expression in the adipose tissue of adult, obese mice. Mice with a partial or complete deficiency of Hmgic resisted diet-induced obesity. Disruption of Hmgic caused a reduction in the obesity induced by leptin deficiency (Lepob/Lepob) in a gene-dose–dependent manner. Our studies implicate a role for HMGIC in fat-cell proliferation, indicating that it may be an adipose-specific target for the treatment of obesity.

standard or a high-fat diet (Fig. 2b,c). The Hmgic mutation is recessive, and at 30 weeks of age there was not a significant difference between the weights of Hmgic+/– and wild-type mice fed the standard diet (27.8±1.38 g versus 29.04±1.59 g, P=0.48). Thus, a haploinsufficiency effect was observed between wildtype and Hmgic+/– mice (35.24±1.86 g versus 29.87±2 g, P=0.03), leading to the conclusion that under the stimulus of a high-fat diet, there are phenotypic ramifications of the Hmgic mutation in the heterozygous state. The lack of weight gain cannot be attributed to a decrease in food intake, because daily food consumption was not statistically different between wild type (4.15±0.36 g) and either Hmgic+/– (4.28±0.34 g, P=0.82) or Hmgic–/– (4.02±0.40 g, P=0.70) genotypes. Thus, absence of one or both Hmgic alleles enables mice to resist the obesity that results from a high-fat diet. A second method of obesity induction used the genetic mouse We initially examined gene expression in adipose tissue isolated model17 Lepob/Lepob, which results from the deficiency of the neufrom wild-type mice fed either a standard or a high-fat diet, as the roendocrine hormone leptin18. Double-homozygous mice latter induces obesity14. RT–PCR analysis of RNA isolated from (Hmgic–/–, Lepob/Lepob) were reduced in size compared with the individual fat depots (Fig. 1a) and various adult tissues (data not shown) from mice fed a standard diet confirmed observations15 in human a that Hmgic is not expressed. In contrast, Hmgic expression was detected in RNA isolated from individual fat depots of wild-type mice after one week on a high-fat diet (Fig. 1a). Similarly, Hmgic expression was observed in the individual fat depots of two genetically obese mouse models16,17, Lepob/Lepob and Leprdb/Leprdb (Fig. 1b), but not in other tissues (data not shown). This provided the first indication for a role of Hmgic in obesity. We had generated a specific Hmgic-null mutant8, which allowed us to examine the in vivo effect of Hmgic in obesity. We induced obesity by feeding mice a high-fat diet. After 26 weeks, wildtype mice had developed obesity compared with mice on the standard diet (Fig. 2a). There was not b a statistically significant difference in the final weight of Hmgic–/– or Hmgic+/– mice fed either a

Fig. 1 Hmgic expression in the white adipose tissue (WAT) of obese mice. a, A high-fat diet induces Hmgic expression in adult mice. RT–PCR was performed on total RNA isolated from inguinal (i), parametrial (p), mesenteric (m) and epididymal (e) fat pads of adult wild-type mice (f, female; m, male) fed either a standard (sd) or a high-fat (hfd) diet. Four-week-old mice were weaned (0) and fed the high-fat or the standard diet for one week (1). RNA samples from 12.5 days postcoitum embryos and Hmgic–/– WAT were used as positive and negative controls, respectively, for Hmgic expression (top). We used Gapd as a positive control to determine the quality of total RNA (bottom). b, Hmgic expression in Lepob/Lepob and Leprdb/Leprdb WAT. A similar RT–PCR analysis was performed on total RNA isolated from inguinal, parametrial, mesenteric and epididymal fat pads of adult (8-week-old) Lepob/Lepob, Leprdb/Leprdb and wild-type mice.

Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, USA. Correspondence should be addressed to K.C. (e-mail: [email protected]).

nature genetics • volume 24 • april 2000

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Fig. 2 Hmgic–/– and Hmgic+/– mice are resistant to diet-induced obesity. Growth curves of wild-type (a), Hmgic–/– (b) and Hmgic+/– (c) mice fed either a high-fat or a standard diet are shown. Growth measurements were initiated at six weeks and at least six mice (no sex-related differences were observed) were used for each growth curve. The total weight gain by wild-type mice on the highfat diet was 21% (35.24±1.86 g versus 29.04±1.59 g, P=0.03). *P