Cardiac-specific leptin receptor deletion exacerbates ischaemic heart failure in mice

Maready

American Journal of Physiology-Endocrinology and Metabolism

et al. 2014

Hall ME, Maready MW, Hall JE, Stec DE. Rescue of cardiac leptin receptors in db/db mice prevents myocardial triglyceride accumulation. Am J Physiol Endocrinol Metab 307: E316 -E325, 2014. First published June 17, 2014 doi:10.1152/ajpendo.00005.2014.-Increased leptin levels have been suggested to contribute to cardiac hypertrophy and attenuate cardiac lipid accumulation in obesity, although it has been difficult to separate leptin's direct effects from those caused by changes in body weight and adiposity. To determine whether leptin attenuates cardiac lipid accumulation in obesity or directly causes left ventricular hypertrophy (LVH), we generated a novel mouse model in which the long form of the leptin receptor (LepR) was "rescued" only in cardiomyocytes of obese db/db mice. Reexpression of cardiomyocyte leptin receptors in db/db mice did not cause LVH but reduced cardiac triglycerides and improved cardiac function. Compared with lean wild-type (WT) or db/db-cardiac LepR rescue mice, db/db mice exhibited significantly lower E/A ratio, a measurement of early to late diastolic filling, which averaged 1.5 Ϯ 0.07 in db/db vs. 1.9 Ϯ 0.08 and 1.8 Ϯ 0.11 in WT and db/db-cardiac LepR rescue mice, respectively. No differences in systolic function were observed. Although db/db and db/db-cardiac LepR rescue mice exhibited similar increases in plasma triglycerides, insulin, glucose, and body weight, cardiac triglycerides were significantly higher in db/db compared with WT and db/db cardiac LepR rescue mice, averaging 13.4 Ϯ 4.2 vs. 3.8 Ϯ 1.6 vs. 3.8 Ϯ 0.7 mg/g, respectively. These results demonstrate that despite significant obesity and increases in plasma glucose and triglycerides, db/db cardiac LepR rescue mice are protected against myocardial lipid accumulation. However, we found no evidence that leptin directly causes LVH.

Section: Discussionmentioning

confidence: 99%

Rescue of cardiac leptin receptors indb/dbmice prevents myocardial triglyceride accumulation

Maready

American Journal of Physiology-Endocrinology and Metabolism

et al. 2014

Journal of Biological Chemistry

“…Further support of AMPK as a negative regulator of cardiac growth has been provided by other studies, showing that AMPK signaling is decreased or impaired in hearts from adiponectin or leptin deficient mice. This decrease in AMPK activity exacerbated hypertrophic growth and heart failure following transverse aortic constriction (34) or myocardial infarction (35). In addition, activation of AMPK inhibits protein synthesis associated with cardiac hypertrophy via two independent signaling pathways that are known to mediate protein synthesis in the heart, the mTOR-p70 S6K -40S ribosomal protein S6 and the eEF2 kinase-eEF2 pathways (26).…”

Section: Discussionmentioning

confidence: 99%

“…3, it can also be regulated by other pathways (e.g. PI3K/Akt and MAPK) (29,35). Hence, resistin-induced hypertrophic response is likely to be an AMPK-dependent (Fig.…”

Section: Mtor/p70 S6k Pathway Inhibition Reduces Resistin-induced Hypmentioning

confidence: 99%

Resistin Promotes Cardiac Hypertrophy via the AMP-activated Protein Kinase/Mammalian Target of Rapamycin (AMPK/mTOR) and c-Jun N-terminal Kinase/Insulin Receptor Substrate 1 (JNK/IRS1) Pathways

Kang

Chemaly

Hajjar

et al. 2011

Resistin has been suggested to be involved in the development of diabetes and insulin resistance. We recently reported that resistin is expressed in diabetic hearts and promotes cardiac hypertrophy; however, the mechanisms underlying this process are currently unknown. Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. Overexpression of resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of AMP-activated protein kinase (AMPK) activity, activation of tuberous sclerosis complex 2/mammalian target of rapamycin (mTOR) pathway, and increased cell size, S6K , a downstream kinase target of mTOR, and increased phosphorylation of the IRS1 serine 636/639 residues, whereas treatment with rapamycin reduced the phosphorylation of these residues. Interestingly, these in vitro signaling pathways were also operative in vivo in ventricular tissues from adult rat hearts overexpressing resistin. These data demonstrate that resistin induces cardiac hypertrophy and myocardial insulin resistance, possibly via the AMPK/mTOR/p70 S6K and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways.

“…In addition, leptin induces catabolism in skeletal muscle through inhibition of insulin signaling and consequent decrease in glucose uptake, which in turn leads to increased fatty acid metabolism. Leptin levels are elevated in obesity (likely due to peripheral resistance to leptin), MI, and HF [32,38]. Leptin and its ObR receptor expression are upregulated in cardiomyocytes in the failing heart, where leptin signaling has cardioprotective effects by increasing signal transducer and activator of transcription (STAT) 3 and adenosine monophosphate-activated protein kinase (AMPK) activation, leading to a decrease in cardiac hypertrophy, apoptosis, and inflammation [38].…”

Section: Endocrine Biomarkersmentioning

confidence: 99%

“…Leptin levels are elevated in obesity (likely due to peripheral resistance to leptin), MI, and HF [32,38]. Leptin and its ObR receptor expression are upregulated in cardiomyocytes in the failing heart, where leptin signaling has cardioprotective effects by increasing signal transducer and activator of transcription (STAT) 3 and adenosine monophosphate-activated protein kinase (AMPK) activation, leading to a decrease in cardiac hypertrophy, apoptosis, and inflammation [38]. Leptin levels go down with mechanical unloading in HF [39].…”

Section: Endocrine Biomarkersmentioning

confidence: 99%

Novel Biomarkers in Acute Heart Failure

Yanavitski

Givertz

2011

Curr Heart Fail Rep

Heart failure goes beyond mechanical dysfunction and involves an interplay of multiple pathophysiologic mechanisms, including inflammation, tissue remodeling, neurohormonal and endocrine signaling, and interactions with the renal and nervous systems. This article highlights some novel biomarkers that may aid in diagnosis, treatment, and prognosis of acute heart failure, specifically focusing on ST2, endoglin, galectin-3, cystatin C, neutrophil gelatinase-associated lipocalin, midregional pro-adrenomedullin, chromogranin A, adiponectin, resistin, and leptin and their emerging clinical roles.