FABP4 is secreted from adipocytes by adenyl cyclase-PKA- and guanylyl cyclase-PKG-dependent lipolytic mechanisms

Abstract

Objective: Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes, and elevated plasma FABP4 levels are associated with obesity-mediated metabolic phenotype. Postprandial regulation and secretory signaling of FABP4 have been investigated. Methods: Time courses of FABP4 levels were examined during an oral glucose tolerance test (OGTT; n 5 53) or a high-fat test meal (n 5 35). Effects of activators and inhibitors of adenyl cyclase (AC)-protein kinase A (PKA) signaling and guanylyl cyclase (GC)-protein kinase G (PKG) signaling on FABP4 secretion from mouse 3T3-L1 adipocytes were investigated. Results: FABP4 level significantly declined after the OGTT or a high-fat meal, while insulin level was increased. Treatment with low and high glucose concentration or palmitate for 2 h did not affect FABP4 secretion from 3T3-L1 adipocytes. FABP4 secretion was increased by stimulation of lipolysis using isoproterenol, a b 3 -adrenoceptor agonist (CL316243), forskolin, dibutyryl-cAMP, and atrial natriuretic peptide, and the induced FABP4 secretion was suppressed by insulin or an inhibitor of PKA (H-89), PKG (KT5823), or hormone sensitive lipase (CAY10499). Conclusions: FABP4 is secreted from adipocytes in association with lipolysis regulated by AC-PKA-and GC-PKG-mediated signal pathways. Plasma FABP4 level declines postprandially, and suppression of FABP4 secretion by insulin-induced anti-lipolytic signaling may be involved in this decline in FABP4 level.

Ectopic Fatty Acid–Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury

“…FABP4 is secreted from adipocytes under regulation by the catecholamine‐induced lipolytic signal pathway, although FABP4 lacks an N‐terminal secretory signal sequence 7, 12, 13. The present study showed that secretion of FABP4 from endothelial cells was slightly, but significantly, enhanced by stimulation of isoproterenol, similar to that in the case of adipocytes.…”

“…FABP4 was secreted from HCAECs in a time‐dependent manner (Figure 2I), and the secretion of FABP4 was slightly, but significantly, enhanced in the presence of isoproterenol for 12 and 24 hours, which is known to increase secretion of FABP4 from adipocytes 12, 13. Secretion of FABP4 in the CM of Ad‐FABP4–transfected HCAECs was significantly greater than that in the CM of Ad‐Control–transfected HCAECs (Figure 2J).…”

“…Total protein content of the cell lysate (CL) in a cell lysis buffer, containing 50 mmol/L Tris‐HCl (pH 7.0), 2 mmol/L EGTA, 5 mmol/L EDTA, 30 mmol/L NaF, 10 mmol/L Na 3 VO 4 , 10 mmol/L Na 4 P 2 O 7 , 40 mmol/L β‐glycerophosphate, 0.5% NP‐40, and 1% protease inhibitor cocktail, was assessed by a microplate protein assay based on Lowry's method (Bio‐Rad). FABP4 protein in the CL and CM was determined by Western blotting and analyzed as previously described 13, 28…”

“…It has recently been reported that FABP4 is secreted from adipocytes in association with lipolysis via a nonclassical secretion pathway,12, 13 although there are no typical secretory signal peptides in the sequence of FABP4 5. FABP4 has also been shown to be secreted from macrophages,14 although the predominant contributors of circulating FABP4 are adipocytes rather than macrophages 12.…”

Role of the fatty acid-binding protein 4 in heart failure and cardiovascular disease

“…correlated with adiposity (Xu et al 2006, Ishimura et al 2013. Despite its lack of an N-terminal secretory signal sequence (Furuhashi & Hotamisligil 2008), FABP4 has been reported to be released from adipocytes through additional mechanisms (Coe et al 1999, Scheja et al 1999, Shen et al 1999, Mita et al 2015 and acts as an adipokine in several organs, including the heart (Fig. 2).…”