An increased cardiac fatty acid supply and increased sarcolemmal presence of the long-chain fatty acid transporter CD36 are associated with and contribute to impaired cardiac insulin sensitivity and function. In the present study we aimed at preventing the development of insulin resistance and contractile dysfunction in cardiomyocytes by blocking CD36-mediated palmitate uptake. Insulin resistance and contractile dysfunction were induced in primary cardiomyocytes by 48 h incubation in media containing either 100 nM insulin (high insulin; HI) or 200 μM palmitate (high palmitate; HP). Under both culture conditions, insulin-stimulated glucose uptake and Akt phosphorylation were abrogated or markedly reduced. Furthermore, cardiomyocytes cultured in each medium displayed elevated sarcolemmal CD36 content, increased basal palmitate uptake, lipid accumulation and decreased sarcomere shortening. Immunochemical CD36 inhibition enhanced basal glucose uptake and prevented elevated basal palmitate uptake, triacylglycerol accumulation and contractile dysfunction in cardiomyocytes cultured in either medium. Additionally, CD36 inhibition prevented loss of insulin signalling in cells cultured in HP, but not in HI medium. In conclusion, CD36 inhibition prevents lipid accumulation and lipid-induced contractile dysfunction in cardiomyocytes, but probably independently of effects on insulin signalling. Nonetheless, pharmacological CD36 inhibition may be considered as a treatment strategy to counteract impaired functioning of the lipid-loaded heart.

Understanding how muscle contraction orchestrates insulin-independent muscle glucose transport may enable development of hyperglycemia-treating drugs. The prevailing concept implicates Ca2+ as a key feed forward regulator of glucose transport with secondary fine-tuning by metabolic feedback signals through proteins such as AMPK. Here, we demonstrate in incubated mouse muscle that Ca2+ release is neither sufficient nor strictly necessary to increase glucose transport. Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress-activated signals. Furthermore, artificial stimulation of AMPK combined with passive stretch of muscle is additive and sufficient to elicit the full contraction glucose transport response. These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport during muscle contraction, and call for a major reconsideration of the established Ca2+ centric paradigm.

Background: Contraction of cardiomyocytes up-regulates glucose and fatty acid uptake by GLUT4 and CD36 translocation to the sarcolemma. Results: Silencing of protein kinase D1 abolishes contraction-induced GLUT4 but not CD36 translocation. Conclusion: Protein kinase D1 signaling mediates cardiac glucose but not fatty acid uptake. Significance: Selective stimulation of glucose uptake is beneficial for diabetic hearts characterized by elevated fatty acid uptake.

This chapter summarizes AMPK function in the regulation of substrate and energy metabolism with the main emphasis on carbohydrate and lipid metabolism, protein turnover, mitochondrial biogenesis, and whole-body energy homeostasis. AMPK acts as whole-body energy sensor and integrates different signaling pathway to meet both cellular and body energy requirements while inhibiting energy-consuming processes but also activating energy-producing ones. AMPK mainly promotes glucose and fatty acid catabolism, whereas it prevents protein, glycogen, and fatty acid synthesis.

The fatty acid transporter and scavenger receptor CD36 is increasingly being implicated in the pathogenesis of insulin resistance and its progression towards type 2 diabetes and associated cardiovascular complications. The redistribution of CD36 from intracellular stores to the plasma membrane is one of the earliest changes occurring in the heart during diet induced obesity and insulin resistance. This elicits an increased rate of fatty acid uptake and enhanced incorporation into triacylglycerol stores and lipid intermediates to subsequently interfere with insulin-induced GLUT4 recruitment (i.e., insulin resistance). In the present paper we discuss the potential of CD36 to serve as a target to rectify abnormal myocardial fatty acid uptake rates in cardiac lipotoxic diseases. Two approaches are described: (i) immunochemical inhibition of CD36 present at the sarcolemma and (ii) interference with the subcellular recycling of CD36. Using in vitro model systems of high-fat diet induced insulin resistance, the results indicate the feasibility of using CD36 as a target for adaptation of cardiac metabolic substrate utilization. In conclusion, CD36 deserves further attention as a promising therapeutic target to redirect fatty acid fluxes in the body.