Leptin hypertrophy

NO)-dependent process (Fruhbeck 1999). In this regard, NO production following leptin administration has been shown to be markedly depressed in obese animals (Beltowski et al. 2003). Interestingly, dietary-induced obesity in hypertensive rats results in slower recovery from stress-induced elevations in blood pressure and heart rate which was associated with myocardial hypertrophy and hyperleptinemia (Sedova et al. 2004). 

Leptin has been shown to increase hyperplasia of the murine atrial HL-1 cell line as well as pediatric cardiomyocytes (Tajmir et al. 2004). Activation of ERK and phosphatidylinositol 3-kinase was demonstrated and implicated in the increase in cell number. It should be noted that leptin-induced hypertrophy has also been shown in human pediatric ventricular myocytes which was associated with increased ERK, p38, and JAK phosphorylation (Madani et al. 2006). 

In the cardiovascular system, leptin has been demonstrated to activate components of the MAPK pathways. In cultured neonatal myocytes, ERK1/2 and p38, but not JNK, were activated by leptin inhibiting ERK had no effect, while inhibition of p38 completely inhibited leptin-induced cardiomyocyte hypertrophy (Rajapurohitam et al. 2003). Leptin has also been shown to induce hyperplasia in the immortalized atrial HL-1 cell line via an ERK-dependent pathway (Tajmir et al. 

Stimulation of p38 may also mediate hypertrophic responses to leptin in vascular tissue. Recently, leptin has been shown to produce hypertrophy in aortic smooth muscle which was associated with p38 activation and which was blocked by p38 inhibition whereas neither ERK nor JNK inhibition exerted any effect (Shin et al. 

In cultured rat portal veins, leptin-induced hypertrophy is associated with p38, JNK, and ERK (unpublished data), suggesting that cell signaling mechanisms involved in leptin-induced hypertrophy may reflect the nature of the vascular tissues used to assess leptin-induced hypertrophy. 

Fig. 20.3 Schematic showing a pivotal role of RhoA/ROCK activation as a mediator of leptin-induced hypertrophy and its interaction with p38. Activation of RhoA/ROCK results in increased cofilin phosphorylation and altered actin dynamics as demonstrated by a decreased G/F-actin ratio. Stimulation of this pathway results in an exclusive and selective translocation of p38 MAPK into the nucleus which results in an increased protein synthesis to an as yet to be identified mechanism.

Zeidan et al. 2008) a finding in agreement with our initial observation that leptin-induced hypertrophy can be blocked by p38, but not by ERK inhibition (Rajapuro-hitam et al. 2003). A summary of the potential role of the RhoA/ROCK system in mediating the hypertrophic effect of leptin is shown in Figure 20.3. 

Rajapurohitam, V., Gan, X. T., Kirshenbaum, L. A., and Karmazyn, M. 2003. The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ. Res. 93 277-279. 

Zeidan, A., Purdham, D. M., Rajapurohitam, V., Javadov, S., Chakrabarti, S., and Karmazyn, M. 2005. Leptin induces vascular smooth muscle cell hypertrophy through angiotensin II- and endothelin-1-dependent mechanisms and mediates stretch-induced hypertrophy. J. Pharmacol. Exp. Ther. 315 1075-1084. 

Although leptin is being derived primarily from adipocytes, it is now shown that non adipocyte tissues can be a source of leptin. In fact, gene expression of leptin and its receptors OB-Ra, OB -Rb and OB-Re have been identified in rat heart.46 It is likely that leptin serves an autocrine/paracrine role in regulating cardiac function. Leptin is shown to have a negative inotropic effect and promotes hypertrophy.47, 48 The physiological role of leptin in myocardial ischemia remains unknown. Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis.49... 

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