Impaired cardiac contractile function in ventricular myocytes from leptin-deficient ob/ob obese mice

Abstract

The level of the obese gene product leptin is often positively correlated with body weight, supporting the notion that hyperleptinemia contributes to obesityassociated cardiac dysfunction. However, a link between leptin levels and cardiac function has not been elucidated. This study was designed to examine the role of leptin deficiency (resulting from a point mutation of the leptin gene) in cardiomyocyte contractile function. Mechanical properties and intracellular Ca 2+ transients were evaluated in ventricular myocytes from lean control and leptin-deficient ob/ob obese mice at 12 weeks of age. Cardiac ultrastructure was evaluated using transmission electron microscopy. ob/ob mice were overtly obese, hyperinsulinemic, hypertriglycemic, hypoleptinemic and euglycemic. Ultrastructural examination revealed swelling and disorganization of cristae in mitochondria from ob/ob mouse ventricular tissues. Cardiomyocytes from ob/ob mice displayed reduced expression of the leptin receptor Ob-R, larger cross-sectional area, decreased peak shortening and maximal velocity of shortening/relengthening, and prolonged relengthening but not shortening duration compared with lean counterparts. Consistent with mechanical characteristics, myocytes from ob/ob mice displayed reduced intracellular Ca 2+ release upon electrical stimulus associated with a slowed intracellular Ca 2+ decay rate. Interestingly, the contractile aberrations seen in ob/ob myocytes were significantly improved by in vitro leptin incubation. Contractile dysfunction was not seen in age-and gender-matched high fat-induced obese mice. These results suggested that leptin deficiency contributes to cardiac contractile dysfunction characterized by both systolic and diastolic dysfunction, impaired intracellular Ca 2+ hemostasis and ultrastructural derangement in ventricular myocytes.

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch

“…Tibia length was similar between the lean and Lep/Lep mice, excluding potential contribution from developmental factor. Cardiac hypertrophy has been shown in Lep/Lep hearts from 8-and 12-week-old mice [40,41], in agreement with our observation of increased absolute heart weight, ratio of heart weight to tibia length and enlarged cross-sectional area of myocytes. Myocardial remodelling is a critical factor in the transition of the heart from a compensated to a decompensated state and may contribute to compromised cardiac function and the MHC isozyme switch [42].…”

“…In addition, the Lep/Lep mice displayed interrupted leptin signalling and reduced leptin receptor LEPR Insets: representative immunoblots using specific antibodies against p47 phox and gp91 phox subunits. Mean±SEM, n=6, *p<0.05 vs lean control, #p<0.05 vs angiotensin II treatment group [41], representing a unique model of obesity. Most obese or overweight individuals display enhanced rather than reduced plasma levels of leptin, contrary to the leptindeficient status in Lep/Lep obesity [4].…”

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…In ob/ob mice aged 12 weeks a qualitative examination revealed mitochondrial swelling and cristae disorganization (Dong et al. 2006). Mitochondrial content and size reflect the interplay between mitophagy (i.e., the degradation of existing, potentially damaged, mitochondria), biogenesis, and fusion/fission events.…”

Mitochondrial Morphology in Metabolic Diseases

“…In all models tested, except Akita mice where oxidative stress was not observed, cardiac and mitochondrial functions were decreased (9,10,16,18,19,41,53,73,80,96,122,123), and these decreases were associated with increases in oxidative stress (10,125,142,143). The OVE26 mouse model develops a type 1 diabetic phenotype through the overexpression of calmodulin, specifically in pancreatic b-cells, leading to damage and extremely low levels of insulin secretion (48).…”