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

J. Eduardo Rame, Lili A. Barouch, Michael N. Sack, Edward G. Lynn, Mones Abu-Asab, Maria Tsokos, Steven J. Kern, Jennifer J. Barb, Peter J. Munson, Marc K. Halushka, Karen L. Miller, Karen Fox-Talbot, Jianhua Zhang, Joshua Hare, Michael A. Solomon, Robert L. Danner

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)726-738
Number of pages13
JournalPhysiological Genomics
Volume43
Issue number12
DOIs
StatePublished - Jun 1 2011

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Caloric Restriction
Peroxisome Proliferator-Activated Receptors
Leptin
Fatty Acids
Heart Failure
Lipids
Nonesterified Fatty Acids
Electron Microscopy
Left Ventricular Hypertrophy
Genes
Echocardiography
Triglycerides
Oxidative Stress
Cell Death
Body Weight
Apoptosis
Staining and Labeling

Keywords

  • Cardiac metabolism
  • Glycerolipid/free fatty acid metabolism
  • Leptin
  • Lipotoxicity
  • Peroxisome proliferator-activated receptor
  • Peroxisome proliferator-activated receptor γ coactivator

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Caloric restriction in leptin deficiency does not correct myocardial steatosis : Failure to normalize PPARα/PGC1α and thermogenic glycerolipid/fatty acid cycling. / Eduardo Rame, J.; Barouch, Lili A.; Sack, Michael N.; Lynn, Edward G.; Abu-Asab, Mones; Tsokos, Maria; Kern, Steven J.; Barb, Jennifer J.; Munson, Peter J.; Halushka, Marc K.; Miller, Karen L.; Fox-Talbot, Karen; Zhang, Jianhua; Hare, Joshua; Solomon, Michael A.; Danner, Robert L.

In: Physiological Genomics, Vol. 43, No. 12, 01.06.2011, p. 726-738.

Research output: Contribution to journalArticle

Eduardo Rame, J, Barouch, LA, Sack, MN, Lynn, EG, Abu-Asab, M, Tsokos, M, Kern, SJ, Barb, JJ, Munson, PJ, Halushka, MK, Miller, KL, Fox-Talbot, K, Zhang, J, Hare, J, Solomon, MA & Danner, RL 2011, 'Caloric restriction in leptin deficiency does not correct myocardial steatosis: Failure to normalize PPARα/PGC1α and thermogenic glycerolipid/fatty acid cycling', Physiological Genomics, vol. 43, no. 12, pp. 726-738. https://doi.org/10.1152/physiolgenomics.00088.2010
Eduardo Rame, J. ; Barouch, Lili A. ; Sack, Michael N. ; Lynn, Edward G. ; Abu-Asab, Mones ; Tsokos, Maria ; Kern, Steven J. ; Barb, Jennifer J. ; Munson, Peter J. ; Halushka, Marc K. ; Miller, Karen L. ; Fox-Talbot, Karen ; Zhang, Jianhua ; Hare, Joshua ; Solomon, Michael A. ; Danner, Robert L. / Caloric restriction in leptin deficiency does not correct myocardial steatosis : Failure to normalize PPARα/PGC1α and thermogenic glycerolipid/fatty acid cycling. In: Physiological Genomics. 2011 ; Vol. 43, No. 12. pp. 726-738.
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AU - Sack, Michael N.

AU - Lynn, Edward G.

AU - Abu-Asab, Mones

AU - Tsokos, Maria

AU - Kern, Steven J.

AU - Barb, Jennifer J.

AU - Munson, Peter J.

AU - Halushka, Marc K.

AU - Miller, Karen L.

AU - Fox-Talbot, Karen

AU - Zhang, Jianhua

AU - Hare, Joshua

AU - Solomon, Michael A.

AU - Danner, Robert L.

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N2 - Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

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