Identification of Fat Mass and Obesity Associated (FTO) Protein Expression in Cardiomyocytes: Regulation by Leptin and Its Contribution to Leptin-Induced Hypertrophy

Abstract

The recently-identified fat mass and obesity-associated (FTO) protein is associated with various physiological functions including energy and body weight regulation. Ubiquitously expressed, FTO was identified in heart homogenates although its function is unknown. We studied whether FTO is specifically expressed within the cardiac myocyte and its potential role pertaining to the hypertrophic effect of the adipokine leptin. Most experiments were performed using cultured neonatal rat cardiomyocytes which showed nuclei-specific FTO expression. Leptin significantly increased FTO expression which was associated with myocyte hypertrophy although both events were abrogated by FTO knockdown with siRNA. Administration of a leptin receptor antibody to either normal or obese rats significant reduced myocardial FTO protein expression. Responses in cardiomyocytes were accompanied by JAK2/STAT3 activation whereas JAK2/STAT3 inhibition abolished these effects. Expression of the cut-like homeobox 1(CUX1) transcriptional factor was significantly increased by leptin although this was restricted to the cathepsin L-dependent, proteolytically-derived shorter p110CUX1 isoform whereas the longer p200CUX1 protein was not significantly affected. Cathepsin L expression and activity were both significantly increased by leptin whereas a cathepsin L peptide inhibitor or siRNA specific for CUX1 completely prevented the leptin-induced increase in FTO expression. The cathepsin L peptide inhibitor or siRNA-induced knockdown of either CUX1 or FTO abrogated the hypertrophic response to leptin. Two other pro-hypertrophic factors, endothelin-1 or angiotensin II had no effect on FTO expression and FTO knockdown did not alter the hypertrophic response to either agent. This study demonstrates leptin-induced FTO upregulation in cardiomyocytes via JAK2/STAT3- dependent CUX1 upregulation and suggests an FTO regulatory function of leptin. It also demonstrates for the first time a functional role of FTO in the cardiomyocyte.

DNA methylation and obesity traits: An epigenome-wide association study. The REGICOR study

“…23 Both FTO and RPGRIP1L are located in one of the most important loci related to obesity. 5 Although FTO and RPGRIP1L functions in specific tissues are controversial, 24 some studies suggest that the expression of these genes regulates appetite by modulating leptin sensitivity at the hypothalamus: a decrease in their expression reduces the sensitivity to leptin, increasing appetite and food intake and contributing to an increase in body weight. 25 Our study found that hypermethylation in a CpG on CUX1 is associated with higher BMI, while the recent meta-analysis reported another CpG on CUX1 with an inverse effect on BMI.…”

Thyrotropin-releasing hormone overexpression induces structural changes of the left ventricle in the normal rat heart

“…Interestingly, several cardiac pathologies have shown increased cardiac fibrosis, with ECM expansion, myocyte hypertrophy, and apoptosis; examples include infarct and obesity with hyperleptinemia, where TRH hyperactivity has been observed (13,5). In these situations where the cardiac TRH system is upregulated, it appears that its inhibition may be protective for the heart.…”

The Demethylase Activity of FTO (Fat Mass and Obesity Associated Protein) Is Required for Preadipocyte Differentiation

“…FTO is ubiquitously expressed, with highest levels in brain and hypothalamus [ 1 , 2 , 11 ]. Although much attention has been devoted to FTO function in brain/hypothalamus [ 8 , 11 , 19 – 24 ], studies beyond the central nervous system are emerging [ 25 , 26 ]. Adipose tissue is the primary site for lipid storage, and acts as an endocrine organ regulating energy status via secreting and responding to hormones[ 27 ].…”