Angiopoietin-like protein 4 is an exercise-induced hepatokine in humans, regulated by glucagon and cAMP

Abstract

ObjectiveAngiopoietin-like protein-4 (ANGPTL4) is a circulating protein that is highly expressed in liver and implicated in regulation of plasma triglyceride levels. Systemic ANGPTL4 increases during prolonged fasting and is suggested to be secreted from skeletal muscle following exercise.MethodsWe investigated the origin of exercise-induced ANGPTL4 in humans by measuring the arterial-to-venous difference over the leg and the hepato-splanchnic bed during an acute bout of exercise. Furthermore, the impact of the glucagon-to-insulin ratio on plasma ANGPTL4 was studied in healthy individuals. The regulation of ANGPTL4 was investigated in both hepatic and muscle cells.ResultsThe hepato-splanchnic bed, but not the leg, contributed to exercise-induced plasma ANGPTL4. Further studies using hormone infusions revealed that the glucagon-to-insulin ratio is an important regulator of plasma ANGPTL4 as elevated glucagon in the absence of elevated insulin increased plasma ANGPTL4 in resting subjects, whereas infusion of somatostatin during exercise blunted the increase of both glucagon and ANGPTL4. Moreover, activation of the cAMP/PKA signaling cascade let to an increase in ANGPTL4 mRNA levels in hepatic cells, which was prevented by inhibition of PKA. In humans, muscle ANGPTL4 mRNA increased during fasting, with only a marginal further induction by exercise. In human muscle cells, no inhibitory effect of AMPK activation could be demonstrated on ANGPTL4 expression.ConclusionsThe data suggest that exercise-induced ANGPTL4 is secreted from the liver and driven by a glucagon-cAMP-PKA pathway in humans. These findings link the liver, insulin/glucagon, and lipid metabolism together, which could implicate a role of ANGPTL4 in metabolic diseases.

Intact regulation of muscle expression and circulating levels of myokines in response to exercise in patients with type 2 diabetes

“…In agreement with previous exercise studies in nondiabetic individuals (Kersten et al 2009;Catoire et al 2014a,b;Norheim et al 2014;Ingerslev et al 2017), we are the first to demonstrate an intact upregulation of muscle ANGPTL4 mRNA and increase in circulating ANGPTL4 in response to acute exercise and further 3-h into recovery in patients with T2D. Experimental work in mice and humans have provided evidence that exercise markedly induces expression of ANGPTL4 in both adipose tissue and liver, and that ANGPTL4 is mainly released from the liver in response to exercise (Norheim et al 2014;Ingerslev et al 2017). These data suggest that other tissues may contribute more than skeletal muscle to the exerciseinduced increase in circulating ANGPTL4.…”

“…; Ingerslev et al. ), we are the first to demonstrate an intact upregulation of muscle ANGPTL4 mRNA and increase in circulating ANGPTL4 in response to acute exercise and further 3‐h into recovery in patients with T2D. Experimental work in mice and humans have provided evidence that exercise markedly induces expression of ANGPTL4 in both adipose tissue and liver, and that ANGPTL4 is mainly released from the liver in response to exercise (Norheim et al.…”

“…; Ingerslev et al. ). These data suggest that other tissues may contribute more than skeletal muscle to the exercise‐induced increase in circulating ANGPTL4.…”

“…The limitations of our study include a small study cohort, the lack of a lean, healthy group to exclude the possibility that obesity/overweight itself causes exercise resistance, as well as lack of inclusion of women in both study groups in order to rule out gender-specific effects of exercise on the examined myokines. Moreover, access to adipose tissue biopsies as well as the application of measurements of the arterial-to-venous difference over the leg and the hepato-splanchnic bed would have been helpful to determine the origin of the examined myokines in response to exercise (Hansen et al 2016;Ingerslev et al 2017).…”

“…CHI3L1 (or YKL-40) is a glycoprotein, which has been reported to inhibit TNFa-induced inflammation and insulin resistance in human skeletal muscle cells . Several studies in mice and healthy humans have shown increased muscle gene expression and circulating levels of CHI3L1 and ANGPTL4 in response to acute exercise (Kersten et al 2009;Catoire et al 2014a,b;Gorgens et al 2016;Ingerslev et al 2017). Some (Ozaki et al 2005;Catoire et al 2014b), but not all studies (Kim et al 2013) in mice and healthy humans have observed increased muscle gene expression of FGF21 in response to acute exercise, whereas circulating levels of FGF21 are consistently reported to be increased in response to acute exercise (Kim et al 2013;Hansen et al 2016;Tanimura et al 2016).…”