High‐fat Diet‐induced Obesity Leads to Resistance to Leptin‐induced Cardiomyocyte Contractile Response

Abstract

Levels of the obese gene product leptin are often elevated in obesity and may contribute to obesity-induced cardiovascular complications. However, the role of leptin in obesity-associated cardiac abnormalities has not been clearly defined. This study was designed to determine the influence of high-fat diet-induced obesity on cardiac contractile response of leptin. Mechanical and intracellular Ca 2+ properties were evaluated using an IonOptix system in cardiomyocytes from adult rats fed low-and high-fat diets for 12 weeks. Cardiomyocyte contractile and intracellular Ca 2+ properties were examined including peak shortening, duration and maximal velocity of shortening/relengthening (TPS/TR 90 , ±dl/dt), Fura-2-fluorescence intensity change (ΔFFI), and intracellular Ca 2+ decay rate (τ). Expression of the leptin receptor (Ob-R) was evaluated by western blot analysis. High-fat diet increased systolic blood pressure and plasma leptin levels. PS and ±dl/dt were depressed whereas TPS and TR 90 were prolonged after high-fat diet feeding. Leptin elicited a concentration-dependent (0-1,000 nmol/l) inhibition of PS, ±dl/dt, and ΔFFI in low-fat but not high-fat diet-fed rat cardiomyocytes without affecting TPS and TR 90 . The Janus kinase 2 (JAK2) inhibitor AG490, the mitogenactivated protein kinase (MAPK) inhibitor SB203580, and the nitric oxide synthase (NOS) inhibitor L-NAME abrogated leptin-induced cardiomyocyte contractile response in low-fat diet group without affecting the high-fat diet group. High-fat diet significantly downregulated cardiac expression of Ob-R. Elevation of extracellular Ca 2+ concentration nullified obesity-induced cardiomyocyte mechanical dysfunction and leptin-induced depression in PS. These data indicate presence of cardiac leptin resistance in diet-induced obesity possibly associated with impaired leptin receptor signaling.

Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia

“…This benefit may be lost in obese patients as central leptin resistance precludes the use of leptin to induce weight loss and normalize lipid profile. Emerging evidence suggests that the peripheral actions of leptin on cardiac myocytes and endothelial cells are also attenuated in diet-induced obesity (36,37). Our results corroborate other evidence that suggests hyperleptinemia found in obesity and sleep-disordered breathing may be more reflective of a general state of leptin resistance.…”

Structural lesions and changing pattern of expression of genes encoding cardiac muscle proteins are associated with ventricular myocyte dysfunction in type 2 diabetic Goto-Kakizaki rats fed a high-fat diet

“…Previous studies, in older rats eating normal rat chow, have demonstrated unaltered amplitude of shortening and reduced time course of relaxation in myocytes from GK rats compared with age-matched control animals (Howarth et al 2007). Interestingly, some previous experiments performed in healthy rats have shown that HFDs resulted in depressed peak myocyte shortening and prolonged time course of shortening and relengthening (Relling et al 2006;Ren et al 2008), and sucrose-enriched diet resulted in prolonged time course of myocyte shortening (Howarth et al 2004).…”

“…For comparison, typical non-fasting blood glucose values in age-matched control Wistar rats would be 107 ± 3 mg dl −1 (FC Howarth, MA Qureshi & ZHH Sobhy, unpublished data). Interestingly, some previous studies have reported that rats and C57BL/6 mice fed HFD for prolonged periods develop insulin resistance and mildly elevated blood glucose (Farley et al 2003;Ren et al 2008).…”

Influência do tempo de exposição à obesidade sobre a função cardíaca de ratos

“…Nossos resultados estão em concordância com autores que verificaram que a obesidade induzida por dietas ricas em gordura eleva as concentrações de leptina; no entanto, a maioria destes estudos encontram resistência à ação deste hormônio, acarretando hiperfagia. (59,111) Dietas ricas em gorduras têm sido extensivamente usadas em roedores para fornecer modelos experimentais de síndrome metabólica que, associam, entre outros, obesidade e dislipidemias. (171) Neste estudo, a obesidade não modificou de maneira consistente o perfil lipídico ao longo dos três períodos de tratamento.…”

“…Contudo, a relação entre disfunção cardíaca e ciclo de Ca +2 intracelular é pouco estudada na obesidade. (50,52,59,74) O trânsito de Ca +2 intracelular é um dos principais mecanismos reguladores da contração e relaxamento miocárdico. (75,76) A contração cardíaca inicia-se a nível celular, com A entrada dos íons cálcio pelos canais L dentro dos cardiomiócitos é bem descrita na literatura como sendo o evento inicial do processo acoplamento excitação-contração.…”