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

This study aimed to assess whether diabetes mellitus (DM) or obesity is an independent risk factor for severe coronavirus disease 2019 (COVID-19) outcomes and to explore whether the risk conferred by one condition is modified by the other. Methods: This retrospective cohort study of inpatient adults with COVID-19 used multivariable Cox regression to determine the independent effects of DM and obesity on the composite outcome of intubation, intensive care unit admission, or in-hospital mortality. Effect modification between DM and obesity was assessed with a statistical interaction term and an exploration of stratum-specific effects. Results: Out of 3,533 patients, a total of 1,134 (32%) had DM, 1,256 (36%) had obesity, and 430 (12%) had both. DM and obesity were independently associated with the composite outcome (hazard ratio [HR] 1.14 [95% CI: 1.01-1.30] and HR 1.22 [95% CI: 1.05-1.43], respectively). A statistical trend for potential interaction between DM and obesity was observed (P = 0.20). Stratified analyses showed potential increased risk with obesity compared with normal weight among patients with DM (HR 1.34 [95% CI: 1.04-1.74]) and patients without DM (HR 1.18 [95% CI: 0.96-1.43]). Conclusions: DM and obesity are independent risk factors associated with COVID-19 severity. Stratified analyses suggest that obesity may confer greater risk to patients with DM compared with patients without DM, and this relationship requires further exploration.

In chronic obesity, activated adipose tissue pro-inflammatory cascades are tightly linked to metabolic dysfunction. Yet, close temporal analyses of the responses to obesogenic environment such as high-fat feeding (HFF) in susceptible mouse strains question the causal relationship between inflammation and metabolic dysfunction, and/or raises the possibility that certain inflammatory cascades play adaptive/homeostatic, rather than pathogenic roles. Here we hypothesized that CTRP6, a C1QTNF family member, may constitute an early responder to acute nutritional changes in adipose tissue, with potential physiological roles. Both 3 days high-fat feeding (3dHFF) and acute obesity reversal (2 weeks switch to low-fat diet after 8w-HFF) already induced marked changes in whole-body fuel utilization. While adipose tissue expression of classical pro-inflammatory cytokines (Tnf-α, Ccl2, Il1b) exhibited no, or only minor, change, C1qtnf6 uniquely increased, and decreased, in response to 3dHFF and acute obesity reversal, respectively. CTRP6 knockout (KO) mouse embryonic fibroblasts (MEF) exhibited increased adipogenic gene expression (Pparg, Fabp4, Adipoq) and markedly reduced inflammatory genes (Tnf-α, Ccl2, Il6) compared to wild-type MEF, and recombinant CTRP6 induced the opposite gene expression signature, as assessed by RNA-sequencing. Consistently, 3dHFF of CTRP6-KO mice induced a greater whole-body and adipose tissue weight gain compared to wild-type littermates. Collectively, we propose CTRP6 as a gene that rapidly responds to acute changes in caloric intake, acting in acute over-nutrition to induce a "physiological inflammatory response" that limits adipose tissue expansion.