Inter-tissue communication via endocrine signals is crucial for appropriate regulation of systemic metabolism and energy homeostasis. Disruptions in tissue crosstalk occur in obesity and other metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). Specifically, changes in liver-secreted proteins (i.e., hepatokines) in NAFLD were previously shown to induce metabolic dysregulation. On the other hand, exercise training increases energy expenditure and can reduce NAFLD severity. However, exercise-induced changes in hepatokine secretion and whether such endocrine remodelling contributes to the beneficial effects of physical activity on energy expenditure (EE) is unknown. Here, we aimed to identify novel exercise-responsive hepatokines and assess their impact on aspects of adiposity and energy balance in mice.
Mice were fed a high-fat diet (HFD) for six weeks to induce obesity and NAFLD and remained sedentary or were endurance exercise trained for a further six weeks. Hepatocytes were isolated three days after their last exercise bout, and changes in the secreted proteome were identified by label-free mass spectrometry. We identified 1590 hepatokines, 102 were classically secreted and markedly altered following exercise training. Syndecan-4 was identified as a novel exercise-responsive hepatokine. Hepatic syndecan-4 was implicated in controlling EE in drosophila, hence, we aimed to determine whether overexpression of syndecan-4 in the livers of obese mice can increase EE and reduce adiposity.
Mice were fed a HFD for six weeks and injected intravenously with an adenoassociated virus to increase syndecan-4 expression specifically in the liver. Six weeks later, adiposity (MRI) and energy expenditure was assessed. Syndecan-4 expression was increased 2-fold in the liver and did not impact adiposity, whole-body substrate utilisation, EE, food intake, liver lipid and glucose metabolism, or NAFLD severity. Taken together, we provide a novel resource describing changes in hepatokine secretion following exercise training and identify syndecan-4 as an exercise-induced hepatokine that does not control energy balance.