Uncoupling protein-3 expression in skeletal muscle and free fatty acids in obesity

Abstract

The newly identified mitochondrial uncoupling proteins UCP2 and UCP3, by contrast with UCP1, are highly expressed in human beings, UCP2 being ubiquitous and UCP3 specific to skeletal muscle. Because of its tissue distribution, UCP3 might have an important role in wholebody energy homoeostasis in human beings. Variations in its degree of expression might contribute to the interindividual variability in resting energy expenditure and in the energybalance dysregulation found in obesity and type 2 diabetes. We investigated whether mRNA expression of UCP2 and UCP3 in human vastus lateralis muscle was correlated with variables related to fat or glucose metabolism and with resting energy expenditure in a mixed population of obese patients and obese patients with type 2 diabetes. Nine obese, 10 h fasted patients, including three with type 2 diabetes (untreated but dietetically controlled, fasting plasma glucose of 8·1 to 10·5 mmol/L, table), volunteered, with written consent, to participate, which was accepted by the local Human Investigation Committee. We measured lean body mass with bioelectrical impedance. Plasma glucose concentrations were determined with a Beckman Glucose Analyzer II (Beckman Instruments, CA, USA), and plasma free fatty acids and insulin concentrations with commercial kits (Wako Chemicals GmbH, Germany, and Abbott, IL). Glucose uptake was measured with a euglycaemic hyperinsulinaemic clamp, and glucose and lipid oxidation rates, as well as resting energy expenditure, were determined by indirect calorimetry. The concentrations of UCP2 and UCP3 mRNA in vastus lateralis biopsy fragments were measured by northern blot. The expression of UCP2 and UCP3 mRNA normalised to the respective concentrations of 18S rRNA were compared with 12 physical, biological, and metabolic variables and analysed (Simple Pearson ProductMoment correlations). The mRNA expression of UCP3 was positively and linearly correlated with circulating free fatty acids (r=0·83; p=0·005), whereas that of UCP2 was not (r=0·40). When adjustments were made for age, percentage of fat mass, body-mass index, lean body mass and bodyweight, the correlation between UCP3 mRNA and concentrations of free fatty acids was stronger (r=0·99; p 0·05) was seen between UCP2 or UCP3 mRNA expression and age, percentage fat mass, body-mass index, lean body mass, resting energy expenditure per kg lean body mass, bodyweight, fasting plasma glucose, insulin concentrations, insulin-induced glucose uptake, glucose oxidation, and lipid oxidation. Free fatty acids might control muscle UCP3 expression. A 10-day severe calorie restriction increases muscle UCP2 and UCP3 mRNA expression, and in rodents infusion of free fatty acids increases muscle UCP3 mRNA. Our data suggest a role for muscle UCP3 in the metabolic adaptations to increases in fatty-acid supply, and, therefore, the involvement of UCP3 in a compensatory mechanism linking obesity to increased muscle thermogenesis.