Nur77 Regulates Lipolysis in Skeletal Muscle Cells

Abstract

Skeletal muscle is a major mass peripheral tissue that accounts for ϳ40% of total body weight and 50% of energy expenditure and is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. Excessive caloric intake is sensed by the brain and induces ␤-adrenergic receptor (␤-AR)-mediated adaptive thermogenesis. ␤-AR null mice develop severe obesity on a high fat diet. However, the target gene(s), target tissues(s), and molecular mechanism involved remain obscure. We observed that 30 -60 min of ␤-AR agonist (isoprenaline) treatment of C2C12 skeletal muscle cells strikingly activated (>100-fold) the expression of the mRNA encoding the nuclear hormone receptor, Nur77. In contrast, the expression of other nuclear receptors that regulate lipid and carbohydrate metabolism was not induced. Stable transfection of Nur77-specific small interfering RNAs (siNur77) into skeletal muscle cells repressed endogenous Nur77 mRNA expression. Moreover, we observed attenuation of gene and protein expression associated with the regulation of energy expenditure and lipid homeostasis, for example AMP-activated protein kinase ␥3, UCP3, CD36, adiponectin receptor 2, GLUT4, and caveolin-3. Attenuation of Nur77 expression resulted in decreased lipolysis. Finally, in concordance with the cell culture model, injection and electrotransfer of siNur77 into mouse tibialis cranialis muscle resulted in the repression of UCP3 mRNA expression. This study demonstrates regulatory cross-talk between the nuclear hormone receptor and ␤-AR signaling pathways. Moreover, it suggests Nur77 modulates the expression of genes that are key regulators of skeletal muscle lipid and energy homeostasis. In conclusion, we speculate that Nur77 agonists would stimulate lipolysis and increase energy expenditure in skeletal muscle and suggest selective activators of Nur77 may have therapeutic utility in the treatment of obesity.Obesity and fat deposition are primarily controlled by food intake and energy expenditure. Obesity has been linked to the development of heart disease, cancer, and stroke, the top three causes of death in the United States, and has recently been recognized by the World Health Organization as one of the top 10 global health problems. Moreover, obesity leads to metabolic syndrome X, a disorder that includes elevated levels of triglycerides and low density lipoprotein (bad) cholesterol, low levels of high density lipoprotein (good) cholesterol, impaired fasting glucose, and hypertension (2). These are cardiovascular risk factors for diseases such as atherosclerosis and type II diabetes. More than 65% of United States adults are overweight, and Ͼ30% of adults (greater than 61 million people) are clinically obese (1, 2).Diet, lifestyle, metabolism, and genetics are the most significant factors in controlling weight. Current obesity therapies perform modestly and are aimed at central appetite suppression and reduced fat absorption. Recent research su...

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“…The aqueous phase containing 3 H 2 O was collected and subjected to liquid scintillation counting. For the PGE 2 treatment assay, cells were serum-starved for 48 h, and PGE 2 (1 mol/liter) was added for 2 h before the addition of [9, H]palmitic acid.…”

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