Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity.
Disruption of the leptin signaling pathway within the heart causes left ventricular hypertrophy (LVH). Because human obesity is a syndrome of leptin resistance, which is not amenable to leptin treatment, the identification of parallel signal transduction pathways is of potential therapeutic value. Ciliary neurotrophic factor (CNTF), which acts parallel to leptin in the hypothalamus, is not previously recognized to have cardiac activity. We hypothesized that CNTF receptors are present on cardiomyocytes and their activation reverses LVH in both leptin-deficient ob/ob and leptin-resistant db/db mice. The localization of CNTF receptors (CNTFRalpha) to the sarcolemma in C57BL/6, ob/ob and db/db was confirmed in situ with immunohistochemistry, and immunoblotting (60 and 40 kDa) on isolated myocytes. ob/ob mice were randomly assigned to receive s.c. recombinant CNTF (CNTF(Ax15); 0.1 mg x kg(-1) per day; n = 11) calorie-restriction (n = 9), or feeding ad libitum (n = 11). db/db mice were allocated to three similar groups (n = 8, 7, and 8, respectively) plus a leptin group (1 mg x kg(-1) per day; n = 7). Echocardiography showed that CNTF(Ax15) reduced cardiac hypertrophy [posterior wall thickness decreased by 29 +/- 8% (P < 0.01) in ob/ob and by 21 +/- 3% in db/db mice (P < 0.01)], which was consistent with the reduction of myocyte width. Western blotting showed that leptin and CNTF(Ax15) activated Stat3 and ERK1/2 pathway in cultured adult mice cardiomyocytes and cardiac tissue from in ob/ob and db/db mice. Together, these findings support the role of a previously undescribed signaling pathway in obesity-associated cardiac hypertrophy and have therapeutic implications for patients with obesity-related cardiovascular disease and other causes of LVH.
Raju
Shubha V Y
SV
Division of Cardiology and Institute for Cell Engineering, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
Zheng
Meizi
M
Schuleri
Karl H
KH
Phan
Alexander C
AC
Bedja
Djahida
D
Saraiva
Roberto M
RM
Yiginer
Omer
O
Vandegaer
Koenraad
K
Gabrielson
Kathleen L
KL
O'donnell
Christopher P
CP
Berkowitz
Dan E
DE
Barouch
Lili A
LA
Hare
Joshua M
JM
D000818:Animals; D048429:Cell Size / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020738:Leptin / Q000172:deficiency* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009765:Obesity / Q000150:complications*; D020801:Receptor, Ciliary Neurotrophic Factor / Q000187:drug effects / Q000378:metabolism*; D054411:Receptors, Leptin; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction
D020934:Ciliary Neurotrophic Factor; C515448:LEPR protein, human; D020738:Leptin; D020801:Receptor, Ciliary Neurotrophic Factor; D054411:Receptors, Leptin; D011994:Recombinant Proteins; C515447:leptin receptor, mouse