Reduced Cardiac Efficiency and Altered Substrate Metabolism Precedes the Onset of Hyperglycemia and Contractile Dysfunction in Two Mouse Models of Insulin Resistance and Obesity

Abstract

Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine whether changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice). Ob/ob and db/db mice were studied at 4, 8, and 15 wk of age. Four-week-old mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and 15 wk. In isolated working hearts, rates of glucose oxidation were reduced by 28-37% at 4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation rates and myocardial oxygen consumption were increased in 4-wk-old mice of both strains. Fatty acid oxidation rates progressively increased in db/db mice in parallel with the earlier onset and greater duration of hyperglycemia. In vivo, cardiac catheterization revealed significantly increased left ventricular contractility and relaxation (positive and negative dP/dt) in both strains at 4 wk of age. dP/dt declined over time in db/db mice but remained elevated in ob/ob mice at 15 wk of age. Increased beta-myosin heavy chain isoform expression was present in 4-wk-old mice and persisted in 15-wk-old mice. Increased expression of peroxisomal proliferator-activated receptor-alpha regulated genes was observed only at 15 wk in both strains. These data indicate that altered myocardial substrate use and reduced myocardial efficiency are early abnormalities in the hearts of obese mice and precede the onset of hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo, but loss of the hypercontractile phenotype of obesity and up-regulation of peroxisomal proliferator-activated receptor-alpha regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia.

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

“…Furthermore, we studied whether fructose feeding for 6 weeks in the rat would lead to cardiac mitochondrial dysfunction as previously reported in other animal models (Boudina and Abel 2010; Buchanan et al. 2005). Our data show a clear pattern of altered substrate utilization characterized by (1) reduced PDH activity (2) increased sarcolemmal (CD36) and mitochondrial fatty acid uptake (CPT1B), (3) increased State 3 respiration with fatty acid substrates, (4) increased MCAD and β ‐HCAD activities, and (5) increased nuclear expression of PPAR α and PGC1 α , all consistent with predominant reliance of cardiac metabolism on fatty acid utilization.…”

“…As in genetic models of type‐2 diabetes ( ob/ob and db/db mice), PPAR α activation and related changes in expression levels of PPAR α targets such as PDK4 or MCAD appear only after 5 weeks (Buchanan et al. 2005; Wright et al. 2009).…”

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).…”

“…Subsequent studies utilizing succinate and glutamate as substrates determined that Akita mice do have deficiencies in respiration in cardiac tissue, which results in suppressed ATP production (19). This suggests that ROS production may not be required for the development of DCM; however, it may exacerbate the physiological impairment upon metabolic insults, as type 2 models of diabetes demonstrate more robust impairment of contractile function and energetic deficiencies (16,85). Despite the absence of ROS, there is a consistent abnormal mitochondrial morphology in cardiac tissue from these type 1 diabetic genetic mouse models, which correlates with suppressed energy production.…”

Oxidation of intracellular and extracellular fatty acids in skeletal muscle

“…Abnormality in lipid metabolism is implicated in many diseased conditions and thus it is critical for understanding and treatment of diseases. This is exemplified by the intense studies of fatty acid metabolism over the past decades in relation to insulin resistance, a characteristic of a number of diseases such as obesity, type 2 diabetes and other complications [2][3][4][5][6][7]. A focus of these studies is the role of fatty acid oxidation in the impairment of glucose metabolism and insulin resistance, stimulated by the discovery of glucose-fatty acid cycle by Randle and associates in 1963 (hence also termed Randle cycle).…”