Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice.
Transgenic overexpression of CTRP9, a secreted hormone downregulated in obesity, confers striking protection against diet-induced obesity and type 2 diabetes. However, the physiological relevance of this adiponectin-related plasma protein remains undefined. Here, we used gene targeting to establish the metabolic function of CTRP9 in a physiological context. Mice lacking CTRP9 were obese and gained significantly more body weight when fed standard laboratory chow. Increased food intake, due in part to upregulated expression of hypothalamic orexigenic neuropeptides, contributed to greater adiposity in CTRP9 knockout mice. Although the frequency of food intake remained unchanged, CTRP9 knockout mice increased caloric intake by increasing meal size and decreasing satiety ratios. The absence of CTRP9 also resulted in peripheral tissue insulin resistance, leading to increased fasting insulin levels, impaired hepatic insulin signaling, and reduced insulin tolerance. Increased expression of lipogenic genes, combined with enhanced caloric intake, contributed to hepatic steatosis in CTRP9 knockout mice. Loss of CTRP9 also resulted in reduced skeletal muscle AMPK activation and mitochondrial content. Together, these results provide the genetic evidence for a physiological role of CTRP9 in controlling energy balance via central and peripheral mechanisms.
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland;
Zhikui
Z
Wei
Xia
X
Lei
Pia S
PS
Petersen
Susan
S
Aja
G William
GW
Wong
D052242:Adiponectin / Q000235:genetics / Q000502:physiology*; D050154:Adiposity / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000235:genetics; D004435:Eating / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D018390:Gene Targeting; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D052242:Adiponectin; C534692:CTRP9 protein, mouse; D006023:Glycoproteins
C1q/tumor necrosis factor-related protein 9; adipokine; adiponectin; diabetes; energy balance; insulin sensitivity; obesity