Evidence supports an antilipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin-deficient mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction versus leptin repletion in obese leptin-deficient (ob/ob) mice.
Echocardiography was performed on 7 mo old C57BL/6 wild-type mice (WT) and ob/ob mice fed ad libitum, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for 4 wk. Ventricular tissue was examined by electron microscopy (EM), triglyceride (TAG) content, oil red O staining, mitochondrial coupling assay, and microarray expression profiling.
LR and CR-ob/ob mice showed decreased body and heart weight, and LV wall thickness compared with ad libitum ob/ob mice. LV fractional shortening was decreased in ad libitum ob/ob mice, but restored to WT in LR and CR groups. However, myocardial lipid content by EM and TAG analysis revealed persistent cardiac steatosis in the CR-ob/ob group. Although CR restored mitochondrial coupling to WT levels, PPARα was suppressed and genes associated with oxidative stress and cell death were upregulated in CR-ob/ob animals. In contrast, LR eliminated cardiac steatosis, normalized mitochondrial coupling, and restored PGC1α and PPARα expression, while inducing core genes involved in glycerolipid/free fatty acid (GL/FFA) cycling, a thermogenic pathway that can reduce intracellular lipids.
Thus, CR in the absence of leptin fails to normalize cardiac steatosis. GL/FFA cycling may be, at least in part, leptin-dependent and a key pathway that protects the heart from lipid accumulation.
"In accordance with a previous report (14), we observed a significant increase in heart weights in ob/ob and U3OB mice compared with WT and UCP3KO mice (Fig. 3E). Because we previously showed that FA-induced mitochondrial uncoupling was in part responsible for reduced CE in ob/ob and db/db mice (11,17), we hypothesized that deletion of UCP3 protein in ob/ob hearts would reduce cardiac O2 consumption and enhance CE. "
[Show abstract][Hide abstract] ABSTRACT: These studies investigate the role of uncoupling protein 3 (UCP3) in cardiac energy metabolism, cardiac O(2) consumption (MVO(2)), cardiac efficiency (CE), and mitochondrial uncoupling in high fat (HF)-fed or leptin-deficient mice. UCP3KO and wild-type (WT) mice were fed normal chow or HF diets for 10 weeks. Substrate utilization rates, MVO(2), CE, and mitochondrial uncoupling were measured in perfused working hearts and saponin-permeabilized cardiac fibers, respectively. Similar analyses were performed in hearts of ob/ob mice lacking UCP3 (U3OB mice). HF increased cardiac UCP3 protein. However, fatty acid (FA) oxidation rates were similarly increased by HF diet in WT and UCP3KO mice. By contrast, MVO(2) increased in WT, but not in UCP3KO with HF, leading to increased CE in UCP3KO mice. Consistent with increased CE, mitochondrial coupling was increased in the hearts of HF-fed UCP3KO mice. Unexpectedly, UCP3 deletion in ob/ob mice reduced FA oxidation but had no effect on MVO(2) or CE. In addition, FA-induced mitochondrial uncoupling was similarly enhanced in U3OB compared with ob/ob hearts and was associated with elevated mitochondrial thioesterase-1 protein content. These studies show that although UCP3 may mediate mitochondrial uncoupling and reduced CE after HF feeding, it does not mediate uncoupling in leptin-deficient states.
[Show abstract][Hide abstract] ABSTRACT: It is well established that individuals with the metabolic syndrome have a significantly increased risk of cardiovascular disease and much effort has been expended to elicit the underlying mechanisms. Various studies have proposed that excessive or deficient physiological effects mediated by leptin make an important contribution, yet many paradoxical observations often preclude a clear definition of the role of leptin. This review article will briefly discuss principal and most recent evidence on direct and indirect regulation of the cardiovascular system by leptin, focusing on cardiac structural and functional as well as vascular effects.
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