Cardiac hypertrophy is accompanied by molecular remodeling that affects different cellular pathways, including fatty acid (FA) utilization. In the present study, we show that cardiac lipid metabolism is differentially regulated in response to physiological (endurance training) and pathological [abdominal aortic banding (AAB)] hypertrophic stimuli. Physiological hypertrophy was accompanied by an increased expression of lipogenic genes and the activation of sterol regulatory element-binding protein-1c and Akt signaling. Additionally, FA oxidation pathways regulated by AMP-activated protein kinase (AMPK) and peroxisome proliferator activated receptor-α (PPARα) were induced in trained hearts. Cardiac lipid content was not changed by physiological stimulation, underlining balanced lipid utilization in the trained heart. Moreover, pathological hypertrophy induced the AMPK-regulated oxidative pathway, whereas PPARα and expression of its downstream targets, i.e., acyl-CoA oxidase and carnitine palmitoyltransferase I, were not affected by AAB. In contrast, pathological hypertrophy leads to cardiac triglyceride (TG) and diacylglycerol (DAG) accumulation, although the expression of lipogenic genes and the levels of FA transport proteins (CD36 and FATP) were not changed or reduced compared with the sham group. A possible explanation for this phenomenon is a decrease in lipolysis, as evidenced by the increased content of adipose triglyceride lipase inhibitor G₀S2, the increased phosphorylation of hormone-sensitive lipase at Ser⁵⁶⁵, and the decreased protein levels of DAG lipase that attenuate TG and DAG contents. The increased TG and DAG accumulation observed in AAB-induced hypertrophy might have lipotoxic effects, thereby predisposing to cardiomyopathy and heart failure in the future.

The liver is the major source of glucose production during fasting under normal physiological conditions. However, the kidney may also contribute to maintaining glucose homeostasis in certain circumstances. To test the ability of the kidney to compensate for impaired hepatic glucose production in vivo, we developed a stable isotope approach to simultaneously quantify gluconeogenic and oxidative metabolic fluxes in the liver and kidney. Hepatic gluconeogenesis from phosphoenolpyruvate was disrupted via liver-specific knockout of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; KO). ² H/ ¹³ C isotopes were infused in fasted KO and WT littermate mice, and fluxes were estimated from isotopic measurements of tissue and plasma metabolites using a multicompartment metabolic model. Hepatic gluconeogenesis and glucose production were reduced in KO mice, yet whole-body glucose production and arterial glucose were unaffected. Glucose homeostasis was maintained by a compensatory rise in renal glucose production and gluconeogenesis. Renal oxidative metabolic fluxes of KO mice increased to sustain the energetic and metabolic demands of elevated gluconeogenesis. These results show the reciprocity of the liver and kidney in maintaining glucose homeostasis by coordinated regulation of gluconeogenic flux through PEPCK-C. Combining stable isotopes with mathematical modeling provides a versatile platform to assess multitissue metabolism in various genetic, pathophysiological, physiological, and pharmacological settings.

Disturbances in cardiac lipid metabolism are associated with the development of cardiac hypertrophy and heart failure. Spontaneously hypertensive rats (SHRs), a genetic model of primary hypertension and pathological left ventricular (LV) hypertrophy, have high levels of diacylglycerols in cardiomyocytes early in development. However, the exact effect of lipids and pathways that are involved in their metabolism on the development of cardiac dysfunction in SHRs is unknown. Therefore, we used SHRs and Wistar Kyoto (WKY) rats at 6 and 18 weeks of age to analyze the impact of perturbations of processes that are involved in lipid synthesis and degradation in the development of LV hypertrophy in SHRs with age. Triglyceride levels were higher, whereas free fatty acid (FA) content was lower in the LV in SHRs compared with WKY rats. The expression of de novo FA synthesis proteins was lower in cardiomyocytes in SHRs compared with corresponding WKY controls. The higher expression of genes that are involved in TG synthesis in 6-week-old SHRs may explain the higher TG content in these rats. Adenosine monophosphate-activated protein kinase phosphorylation and peroxisome proliferator-activated receptor α protein content were lower in cardiomyocytes in 18-week-old SHRs, suggesting a lower rate of β-oxidation. The decreased protein content of α/β-hydrolase domain-containing 5, adipose triglyceride lipase (ATGL) activator, and increased content of G0/G1 switch protein 2, ATGL inhibitor, indicating a lower rate of lipolysis in the heart in SHRs. In conclusion, the present study showed that the development of LV hypertrophy and myocardial dysfunction in SHRs is associated with triglyceride accumulation, attributable to a lower rate of lipolysis and β-oxidation in cardiomyocytes.