Myonectin deletion promotes adipose fat storage and reduces liver steatosis

Abstract

We recently described myonectin (also known as erythroferrone) as a novel skeletal muscle‐derived myokine with metabolic functions. Here, we use a genetic mouse model to determine myonectin's requirement for metabolic homeostasis. Female myonectin‐deficient mice had larger gonadal fat pads and developed mild insulin resistance when fed a high‐fat diet (HFD) and had reduced food intake during refeeding after an unfed period but were otherwise indistinguishable from wild‐type littermates. Male mice lacking myonectin, however, had reduced physical activity when fed ad libitum and in the postprandial state but not during the unfed period. When stressed with an HFD, myonectin‐knockout male mice had significantly elevated VLDL‐triglyceride (TG) and strikingly impaired lipid clearance from circulation following an oral lipid load. Fat distribution between adipose and liver was also altered in myonectin‐deficient male mice fed an HFD. Greater fat storage resulted in significantly enlarged adipocytes and was associated with increased postprandial lipoprotein lipase activity in adipose tissue. Parallel to this was a striking reduction in liver steatosis due to significantly reduced TG accumulation. Liver metabolite profiling revealed additional significant changes in bile acids and 1‐carbon metabolism pathways. Combined, our data affirm the physiologic importance of myonectin in regulating local and systemic lipid metabolism.—Little, H. C., Rodriguez, S., Lei, X., Tan, S. Y., Stewart, A. N., Sahagun, A., Sarver, D. C., Wong, G. W. Myonectindeletion promotes adipose fat storage and reduces liver steatosis. FASEB J. 33, 8666–8687 (2019). http://www.fasebj.org

Codon-optimized FAM132b prevents diet-induced obesity by modulating adrenergic response and insulin action

“…This is the first demonstration of a therapeutic effect on metabolic disorders in mice with FAM132b gene therapy. A recent study shows that myonectin (FAM132b) deletion promotes adipose lipid storage and reduces hepatic steatosis (35), consistent with our expectation that FAM132b will be taken as a gene therapy target for metabolic disorders.…”

“…FAM132b (Myonectin) has been identified as a postprandial signal derived from skeletal muscle to integrate metabolic processes in other tissues, and promotes fat transfer from adipocytes to the liver (41). FAM132b-deficient mice exhibited greater fat storage and a striking reduction in liver steatosis (35). Thus, FAM132b gene transfer increases the risk of fatty liver disease by preventing fat accumulation and obesity.…”

C1q/TNF-related protein 2 (CTRP2) deletion promotes adipose tissue lipolysis and hepatic triglyceride secretion

“…Each of the CTRP proteins has a distinct tissue expression profile and a few are highly expressed in adipose tissue (14). Genetic gain-and loss-of-function mouse models indicate overlapping and nonredundant metabolic functions for the C1q family members that have been characterized thus far (7,8,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

Exercise-Released Myokines in the Control of Energy Metabolism

“…Myonectin deletion impairs lipid handling resulting in an increased adipose tissue mass in diet-induced obese mice. However, these changes are independent of modifications in adipose tissue lipolysis in myonectin knockout mice, and are due to increased lipid uptake into adipocytes in postprandial conditions (Little et al, 2019). Furthermore, myonectin does not seem to be required for the physiological responses to exercise in mice (Little et al, 2019).…”