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Identification of fat mass and obesity associated (FTO) protein expression in cardiomyocytes: regulation by leptin and its contribution to leptin-induced hypertrophy.

Gan XT, Zhao G, Huang CX, Rowe AC, Purdham DM, Karmazyn M - PLoS ONE (2013)

Bottom Line: The recently-identified fat mass and obesity-associated (FTO) protein is associated with various physiological functions including energy and body weight regulation.Responses in cardiomyocytes were accompanied by JAK2/STAT3 activation whereas JAK2/STAT3 inhibition abolished these effects.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada.

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.

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Hypertrophic responses to leptin with FTO, CUX1 and cathepsin L (Cath L) inhibition.Cell surface area is shown in the left row whereas expression of ANP and β-MHC are depicted in the middle and right rows, respectively. Note that the hypertrophic responses to leptin were abolished by all treatments. Data are presented as mean+SEM. N = 7. *P<0.05 from respective control values. +P<0.05 from the leptin alone group.
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pone-0074235-g008: Hypertrophic responses to leptin with FTO, CUX1 and cathepsin L (Cath L) inhibition.Cell surface area is shown in the left row whereas expression of ANP and β-MHC are depicted in the middle and right rows, respectively. Note that the hypertrophic responses to leptin were abolished by all treatments. Data are presented as mean+SEM. N = 7. *P<0.05 from respective control values. +P<0.05 from the leptin alone group.

Mentions: Finally, we determined whether approaches aimed at supressing cathepsin L, CUX1 or FTO share an equal ability to attenuate the hypertrophic effect of leptin. As summarized in Figure 8, pharmacological inhibition of cathepsin L or knockdown of either CUX1 or FTO with siRNA prevented the hypertrophic response of cardiomyocytes to leptin. Moreover, these effects of leptin as well as its ability to activate JAK2/STAT3 were completely prevented by the leptin receptor antagonist SHLA (Table 2).


Identification of fat mass and obesity associated (FTO) protein expression in cardiomyocytes: regulation by leptin and its contribution to leptin-induced hypertrophy.

Gan XT, Zhao G, Huang CX, Rowe AC, Purdham DM, Karmazyn M - PLoS ONE (2013)

Hypertrophic responses to leptin with FTO, CUX1 and cathepsin L (Cath L) inhibition.Cell surface area is shown in the left row whereas expression of ANP and β-MHC are depicted in the middle and right rows, respectively. Note that the hypertrophic responses to leptin were abolished by all treatments. Data are presented as mean+SEM. N = 7. *P<0.05 from respective control values. +P<0.05 from the leptin alone group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3760875&req=5

pone-0074235-g008: Hypertrophic responses to leptin with FTO, CUX1 and cathepsin L (Cath L) inhibition.Cell surface area is shown in the left row whereas expression of ANP and β-MHC are depicted in the middle and right rows, respectively. Note that the hypertrophic responses to leptin were abolished by all treatments. Data are presented as mean+SEM. N = 7. *P<0.05 from respective control values. +P<0.05 from the leptin alone group.
Mentions: Finally, we determined whether approaches aimed at supressing cathepsin L, CUX1 or FTO share an equal ability to attenuate the hypertrophic effect of leptin. As summarized in Figure 8, pharmacological inhibition of cathepsin L or knockdown of either CUX1 or FTO with siRNA prevented the hypertrophic response of cardiomyocytes to leptin. Moreover, these effects of leptin as well as its ability to activate JAK2/STAT3 were completely prevented by the leptin receptor antagonist SHLA (Table 2).

Bottom Line: The recently-identified fat mass and obesity-associated (FTO) protein is associated with various physiological functions including energy and body weight regulation.Responses in cardiomyocytes were accompanied by JAK2/STAT3 activation whereas JAK2/STAT3 inhibition abolished these effects.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada.

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.

Show MeSH
Related in: MedlinePlus