Diabesity - novel molecular targets for obesity and type 2 diabetes
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Professor Sven Enerbäck
Medical Genetics
Inst. of Medical Biochemistry
Göteborg University
Box 440
SE-405 30 Goteborg

Professor Sven Enerbäck
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Winged helix gene contribution to organogenesis

FOXC2 is a winged helix gene that protects against obesity hypertriglyceridemia, and insulin resistance Obesity, hyperlipidemia and insulin resistance are common forerunners of non-insulin dependent diabetes mellitus (NIDDM) a serious and increasingly prevalent disease in the industrialised part of the world. Thrifty genes are thought to conserve energy during periods of famine whereas they constitute a risk for developing obesity related conditions, e.g. NIDDM, when energy is abundant. The precise nature of such hypothetical thrifty genes is not known. We have showed that the transcription factor gene FOXC2 is exclusively expressed in white (WAT) and brown (BAT) adipose tissue during postnatal life. In mice over-expressing this gene, solely in WAT and BAT, intra-abdominal WAT has acquired a "brown fat-like" histology. The intra-abdominal WAT depot is reduced (see below) and the interscapular BAT is hypertrophic. Increased FOXC2 expression has a pleiotropic effect on gene expression in BAT and WAT. For instance, the BAT specific gene uncoupling protein-1 (ucp-1) is induced in intra-abdominal WAT and there are also increased steady state levels of mRNAs encoding: beta 1,2 and 3-adrenergic receptors, adipsin, CEBPalpha, PPARgamma, PPARgamma coactivator-1 (PGC-1), insulin receptor, insulin receptor substrate-1 (IRS-1), IRS-2, insulin responsive glucose transporter-4 (GLUT-4) and hormone sensitive lipase (HSL). As a consequence hereof, total body lipid content has decreased from 30% to 10% (p<0.0004) while no significant change in total body weight can be observed, serum triglycerides are down by more than 50% (p<0.004), serum glucose showed a significant 16% reduction (p<0.05), serum insulin levels are decreased by approximately 50% (p<0.03) and levels of free fatty acids (FFA) in serum are down by 27% (p<0.001). In an intravenous glucose tolerance test, mice over-expressing FOXC2, display significantly increased glucose elimination - a sign of increased insulin sensitivity. Even though it is likely that other pathways/genes are involved, the induction of ucp-1 in WAT, the hypertrophy of BAT, the decrease of intra-abdominal WAT depots and the upregulation of mRNAs encoding beta-adrenergic receptors suggest that an increased sensitivity in a beta-adrenergic/cAMP/protein kinase A (PKA) pathway, at least in part, can explain the findings in mice over-expressing FOXC2. We have demonstrated a PKA isozyme switch with increased levels of the regulative subunit RI-alpha. The PKA type I holoenzyme (RIalpha2C2) binds cAMP with higher affinity and activates more easily than the PKA type II enzyme, we have showed that such a shift in cAMP sensitivity exists in adipocytes from animals with an increased expression of FOXC2. Thus, the adipocytes will have a lower threshold for PKA activation by adrenergic stimuli as compared with wild type littermates. Since FOXC2, directly or indirectly, regulates triglyceride metabolism, adrenergic sensitivity and insulin action in adipocytes, in the way described here, it fulfils the criteria for an anti-thrifty gene. To our knowledge FOXC2 is the only known gene that, in a concerted action, can counteract most, if not all, of the symptoms associated with obesity including hypertriglyceridemia and insulin resistance. A likely consequence of such action would be prevention of NIDDM.


Diabesity: Novel molecular targets for obesity and type 2 diabetes
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