The kielin/chordin-like protein (KCP) attenuates high-fat diet-induced obesity and metabolic syndrome in mice

Abdul Soofi,Katherine I Wolf,Margo P Emont,Nathan Qi,Gabriel Martinez-Santibanez,Edward Grimley,Wesam Ostwani,Gregory R Dressler

doi:10.1074/jbc.m116.771428

Abstract

Obesity and its associated complications such as insulin resistance and non-alcoholic fatty liver disease are reaching epidemic proportions. In mice, the TGF-β superfamily is implicated in the regulation of white and brown adipose tissue differentiation. The kielin/chordin-like protein (KCP) is a secreted regulator of the TGF-β superfamily pathways that can inhibit both TGF-β and activin signals while enhancing bone morphogenetic protein (BMP) signaling. However, KCP's effects on metabolism and obesity have not been studied in animal models. Therefore, we examined the effects of KCP loss or gain of function in mice that were maintained on either a regular or a high-fat diet. KCP loss sensitized the mice to obesity and associated complications such as glucose intolerance and adipose tissue inflammation and fibrosis. In contrast, transgenic mice that expressed KCP in the kidney, liver, and adipose tissues were resistant to developing high-fat diet-induced obesity and had significantly reduced white adipose tissue. Moreover, KCP overexpression shifted the pattern of SMAD signaling in vivo, increasing the levels of phospho (P)-SMAD1 and decreasing P-SMAD3. Adipocytes in culture showed a cell-autonomous effect in response to added TGF-β1 or BMP7. Metabolic profiling indicated increased energy expenditure in KCP-overexpressing mice and reduced expenditure in the KCP mutants with no effect on food intake or activity. These findings demonstrate that shifting the TGF-β superfamily signaling with a secreted protein can alter the physiology and thermogenic properties of adipose tissue to reduce obesity even when mice are fed a high-fat diet.

Highlights

Energy balance is critical for maintaining normal body weight and homeostasis
The importance of TGF-␤ superfamily signaling in determining the types of adipose tissue and the effects of a highfat diet (HFD) on obesity and associated complications have been studied in several different experimental model systems epididymal WAT; PPAR␥, peroxisome proliferator-activated receptor ␥; iBAT, interscapular brown adipose tissue; P, phospho-; VO2, oxygen consumption; VCO2, carbon dioxide production; PFA, paraformaldehyde; iWAT, inguinal white adipose tissue; ANOVA, analysis of variance; PGC, peroxisome proliferator-activated receptor-␥ coactivator
Body composition analyses indicated that the difference in body weights on both diets between WT or kcpϪ/Ϫ and the KCP transgenic mice (kcpTg) mice was due in large part to less white adipose tissue in the kcpTg mice with no significant difference in fluid composition (Fig. 1, C and D)

Summary

To whom correspondence should be addressed

Among the most debilitating effects of obesity are inflammation and fibrosis in adipose tissue, liver, and other organs (10 – 13). A deletion of SMAD3 in mice prevented HFD-induced obesity, hepatic steatosis, and insulin resistance with phenotypic changes in WAT tissue that resembled BAT [20]. In mice that express a KCP transgene, a reciprocal shift in the balance of TGF-␤ and BMP signaling made animals more resistant to developing interstitial fibrosis in the kidney [31]. By modulating KCP protein to alter the signaling balance between BMPs and TGF-␤ and associated P-SMADs, fat composition, thermoregulation, and metabolism were all impacted. These data suggest that altering TGF-␤ superfamily signaling by secreted regulatory proteins can attenuate the negative effects of obesity-induced metabolic syndrome

Results

Discussion

Experimental procedures