Article

Caloric restriction in leptin deficiency does not correct myocardial steatosis: Failure to normalize PPARα/PGC1α and thermogenic glycerolipid/fatty acid cycling

Cardiovascular Medicine Division, University of Pennsylvania, Philadelphia, USA.
Physiological Genomics (Impact Factor: 2.37). 03/2011; 43(12):726-38. DOI: 10.1152/physiolgenomics.00088.2010
Source: PubMed

ABSTRACT

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.

Full-text preview

Available from: physiolgenomics.physiology.org
  • Source
    • "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.
    Full-text · Article · Aug 2012 · Diabetes
  • [Show abstract] [Hide abstract]
    ABSTRACT: Chronically-elevated plasma lipid concentrations, particularly when combined with high glucose, elicit a plethora of effects that cause the progressive deterioration of insulin sensitivity and ultimately cellular malfunction or death. This review addresses how metabolic abnormalities in white adipose tissue leading to excessive lipid or abnormal adipokine release can be modified by PPARγ activation. It also discusses the etiology of cardiac lipotoxicity and oxidative stress, in relation to imbalanced lipid delivery and clearance and how PPARα activation can be used to correct some of these effects.
    No preview · Article · Nov 2011 · Current Molecular Pharmacology
  • Source

    Preview · Chapter · Mar 2012
Show more