Apelin Decreases Lipolysis via Gq, Gi, and AMPK-Dependent Mechanisms

Abstract

The release of free fatty acids (FFAs) from adipocytes (i.e. lipolysis) is increased in obesity and is a contributory factor to the development of insulin resistance. A recently identified adipokine, apelin, is up-regulated in states of obesity. Although apelin is secreted by adipocytes, its functions in them remain largely unknown. To determine whether apelin affects lipolysis, FFA, glycerol, and leptin levels, as well as abdominal adiposity, were measured at baseline and after reintroduction of exogenous apelin in apelin-null mice. To examine apelin's effects in vitro, isoproterenol-induced FFA/glycerol release, and hormone-sensitive lipase (HSL) and acetyl CoA carboxylase phosphorylation were investigated in 3T3-L1 cells and isolated wild-type adipocytes. Serum FFA, glycerol, and leptin concentrations, as well as abdominal adiposity, were significantly increased in apelin-null vs. wild-type mice; these changes were ameliorated in response to exogenous apelin. Apelin also reduced isoproterenol-induced FFA release in adipocytes isolated from wild-type but not APJ-null mice. In 3T3-L1 cells and isolated adipocytes, apelin attenuated isoproterenol-induced FFA/glycerol release. Apelin's inhibition was reversed by pertussis toxin, the G(q) inhibitor glycoprotein antagonist 2A, and the AMP-activated protein kinase inhibitors compound C and dorsomorphin. Apelin increased HSL phosphorylation at Ser-565 and also abrogated isoproterenol-induced HSL phosphorylation at Ser-563. Notably, apelin increased acetyl CoA carboxylase phosphorylation, suggesting AMPK activation. In conclusion, apelin negatively regulates lipolysis. Its actions may be mediated by pathways involving G(q), G(i), and AMP-activated protein kinase.

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

“…1) and increases the number of hypertrophied white adipocytes (29). The above proposed notion is consistent with the previous studies in rodents showing that 1) apelin treatment increases body temperature and O 2 consumption (30); 2) apelin treatment or BAT transplantation decreases body adiposity and insulin resistance (9,25); and 3) apelin-knock-out or BAT-ablated mice exhibit increased central adiposity and insulin resistance (7,28).…”

“…Apelin's Stimulatory Effects on Brown Adipogenesis and Browning of White Adipocytes Are Dependent on AMPK and PI3K/Akt Signaling Pathways-We and others have shown that apelin increases Akt and AMPK phosphorylation in white adipocytes (27,28,34). Here, we also found that apelin increased the activation (phosphorylation) of Akt and AMPK in primary rat brown preadipocytes (Fig.…”

“…Apelin promotes insulin sensitivity and glucose utilization in adipose and muscle tissues (26,27). Apelin injection decreases WAT mass and serum triglyceride level in obese mice, whereas apelin knock-out mice have augmented body adiposity and serum free fatty acid levels (28). Apelin also suppresses white adipocyte differentiation and lipolysis (28,29).…”

“…Apelin injection decreases WAT mass and serum triglyceride level in obese mice, whereas apelin knock-out mice have augmented body adiposity and serum free fatty acid levels (28). Apelin also suppresses white adipocyte differentiation and lipolysis (28,29). The antagonistic effects of apelin on dietinduced obesity and insulin resistance are attributable to its stimulation on UCP1 expression in BAT and body energy expenditure (30,31).…”

Apelin Attenuates Oxidative Stress in Human Adipocytes

“…In agreement with the previous reports (39,56,57) that apelin increased activation (phosphorylation) of AMPK Akt, and ERK1/2 in adipocytes (Fig. 5, A-C), in a dose-dependent manner (data not shown).…”