Abstract
C1q/tumor necrosis factor -alpha-related proteins (CTRPs) have been shown to mediate protective cardiovascular effects, but no data exists on their effects on glucose and fatty acid (FA) metabolism in cardiomyocytes. In the present study, adult rat cardiomyocytes and H9C2 cardiomyoblasts were stimulated with various recombinant CTRPs. Glucose or FA uptake, expression of genes involved in glucose or FA metabolism and the role of the AMP-activated protein kinase (AMPK) and Akt were investigated. Although most CTRPs induced an increase in phosphorylation of AMPK and Akt in cardiomyocytes, mainly CTRP2, 7, 9 and 13 induced GLUT1 and GLUT4 translocation and glucose uptake in cardiomyocytes, despite high structural similarities among CTRPs. AMPK inhibition reduced the CTRPs-mediated activation of Akt, while Akt inhibition did not impair AMPK activation. In addition, CTRP2, 7, 9 and 13 mediated strong effects on the expression of enzymes involved in glucose or FA metabolism. Loss of adiponectin receptor 1, which has been suggested to be involved in CTRP-induced signal transduction, abolished the effects of some but not all CTRPs on glucose metabolism. Targeting the AMPK signaling pathway via CTRPs may offer a therapeutic principle to restore glucose homeostasis by acting on glucose uptake independent of the Akt pathway.
Highlights
Adipose tissue is the major storage depot for triglycerides and an endocrine organ that secretes so-called adipokines into circulation
Circulating levels of CTRP1, CTRP3, CTRP9, CTRP12 and CTRP15 were reduced in obese mice [9]; CTRP7 and CTRP9 were shown to be increased in patients with insulin resistance, type 2 diabetes mellitus or metabolic syndrome [10,11], while other C1q/tumor necrosis factor-alpharelated proteins (CTRPs) were reduced in such patients [12]
The PCR data showed (Figure 1A) that, unlike adiponectin that was mainly expressed in adipose tissues, CTRPs were widely expressed in various rat organs/tissues
Summary
Adipose tissue is the major storage depot for triglycerides and an endocrine organ that secretes so-called adipokines into circulation. Adiponectin has direct beneficial effects on cardiomyocytes in several pathological heart conditions, including cardiac hypertrophy, but it preserves cardiomyocyte function by exerting beneficial effects on glucose and lipid metabolism [2,3]. It stimulates basal as well as insulin-stimulated glucose uptake and Akt phosphorylation in cardiomyocytes through an AMP-activated protein kinase (AMPK)and adiponectin receptor-1 and -2 (AdipoR1/2)-dependent mechanism [4]. CTRP9 shares the highest degree of amino acid identity (51%) with the globular domain of adiponectin [7]. Circulating levels of CTRP1, CTRP3, CTRP9, CTRP12 and CTRP15 were reduced in obese mice [9]; CTRP7 and CTRP9 were shown to be increased in patients with insulin resistance, type 2 diabetes mellitus or metabolic syndrome [10,11], while other CTRPs were reduced in such patients [12]
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