CTRP3 deficiency reduces liver size and alters IL-6 and TGFβ levels in obese mice

Abstract

Wolf RM, Lei X, Yang Z, Nyandjo M, Tan SY, Wong GW. CTRP3 deficiency reduces liver size and alters IL-6 and TGF␤ levels in obese mice. Am J Physiol Endocrinol Metab 310: E332-E345, 2016. First published December 15, 2015; doi:10.1152/ajpendo.00248.2015.-C1q/TNF-related protein 3 (CTRP3) is a secreted metabolic regulator whose circulating levels are reduced in human and rodent models of obesity and diabetes. Previously, we showed that CTRP3 infusion lowers blood glucose by suppressing gluconeogenesis and that transgenic overexpression of CTRP3 protects mice against diet-induced hepatic steatosis. Here, we used a genetic loss-of-function mouse model to further address whether CTRP3 is indeed required for metabolic homeostasis under normal and obese states. Both male and female mice lacking CTRP3 had similar weight gain when fed a control low-fat (LFD) or high-fat diet (HFD). Regardless of diet, no differences were observed in adiposity, food intake, metabolic rate, energy expenditure, or physical activity levels between wild-type (WT) and Ctrp3-knockout (KO) animals of either sex. Contrary to expectations, loss of CTRP3 in LFD-or HFD-fed male and female mice also had minimal or no impact on whole body glucose metabolism, insulin sensitivity, and fasting-induced hepatic gluconeogenesis. Unexpectedly, the liver sizes of HFD-fed Ctrp3-KO male mice were markedly reduced despite a modest increase in triglyceride content. Furthermore, liver expression of fat oxidation genes was upregulated in the Ctrp3-KO mice. Whereas the liver and adipose expression of profibrotic TGF␤1, as well as its serum levels, was suppressed in HFD-fed KO mice, circulating proinflammatory IL-6 levels were markedly increased; these changes, however, were insufficient to affect systemic metabolic outcome. We conclude that, although it is dispensable for physiological control of energy balance, CTRP3 plays a previously unsuspected role in modulating liver size and circulating cytokine levels in response to obesity. adipokine; C1q/tumor necrosis factor-related protein; C1q/tumor necrosis factor; fatty liver; obesity; diabetes THE C1Q/TNF-RELATED PROTEIN (CTRP) family comprises 15 secreted plasma proteins of the C1q family, the first seven of which were identified initially on the basis of sequence homology to the globular C1q domain of adiponectin (66); additional members were subsequently described (6, 43, 49, 59 -61, 64, 65). Recent functional studies demonstrated important and distinct roles for CTRPs in regulating glucose and/or lipid metabolism in the peripheral tissues (38 -42, 57-60) as well as having a central role in modulating food intake (6, 7) and adipocyte differentiation in culture (61). Unlike adiponectin, whose expression is restricted to adipocytes (47), CTRP family members are much more widely expressed (65, 66); all are conserved throughout vertebrate evolution (50).Multiple in vitro and in vivo approaches have been used to elucidate the biological function of one member, CTRP3, a secreted plasma protein whose circulating levels ...

C1q/TNF‐Related Protein 3 (CTRP3) Function and Regulation

“…Considered together, these data suggest that the metabolic effects of CTRP3 are specific to the liver, as no changes to metabolism were observed in skeletal muscle in any experimental ( in vivo or in vitro ) model examined. Interestingly, neither transgenic overexpression nor genetic deletion of CTRP3 resulted in a measurable metabolic effect in mice fed a low fat diet (50, 71), which indicates that CTRP3 may function specifically to help regulate metabolism in response to elevated lipid consumption.…”

“…On the other hand, both transgenic overexpression and daily administration of CTRP3 were effective in attenuating high fat diet-induced hepatic insulin resistance and hepatic steatosis (50). Conversely, hepatic triglycerides were elevated in high fat-fed CTRP3 knockout mice when compared to high fat-fed wild-type mice (71). Considered together, these data suggest that the metabolic effects of CTRP3 are specific to the liver, as no changes to metabolism were observed in skeletal muscle in any experimental ( in vivo or in vitro ) model examined.…”

“…In animal models, diet-induced obesity results in decreased CTRP3 levels concurrent with an elevation in TNF and IL-6 (50). Similarly, diet-induced obese Ctrp3-knockout mice have an enhanced elevation of IL-6 and TNF levels (71). Further, transgenic overexpression of CTRP3 attenuates the high-fat diet induced rise in cytokine levels and more than doubles circulating soluble gp130 (sgp130) levels (50).…”

Adipose tissue-derived cytokines, CTRPs as biomarkers and therapeutic targets in metabolism and the cardiovascular system

“…Regulates glucose and lipid metabolism regulates systemic inflammation in obesity and insulin resistance; modulates mitochondrial biogenesis; attenuate liver fibrosis; biomarker for diabetic retinopathy; negative regulator of osteoclastogenesis; independent predictor for atherosclerosis [47,[56][57][58][59][60] 4 Hepatic cells Modulates energy metabolism; novel nutrient-responsive central regulator of food intake and energy balance; reduces colitis; suppresses the pyroptosis of trophoblasts derived from rats with preeclampsia [61][62][63] 5 Adipose tissue, ocular tissue…”

Late‐onset renal hypertrophy and dysfunction in mice lacking CTRP1

“…Total RNA was isolated from whole kidney tissue, reverse transcribed, and subjected to quantitative real‐time PCR analyses using SYBR green method as previously described . Real‐time PCR primers for fibrotic genes ( Col1a1 , Col3a1 , and Col6a1 ), inflammatory genes ( Il‐1β , Il‐6 , and Tgf‐β ), and other genes used in this study are listed in Table S1. Data were normalized to 18S rRNA and expressed as relative mRNA levels using the ∆∆Ct method …”