In human subcutaneous fat cells where alpha2-ARs numerically predominate over beta-ARs, adrenaline-dependent inhibition of lipolysis has been described in vitro. Adrenaline and noradrenaline have a higher affinity for alpha2- than for beta-ARs, suggesting a role for the alpha2-adrenergic pathway in the control of lipolysis in humans.

In collaboration with Vladimir Stich’s laboratory, we have recently investigated the role of alpha2-ARs in situ using microdialysis and in vivo. In healthy volunteers subjected to two bouts of exercice, it was shown that adrenaline contributed to exercise-induced lipolysis although the existence of an alpha2-AR-mediated counteraction was clearly revealed (). We also tested the hypothesis that physiological activation of antilipolytic alpha2-ARs could inhibit lipid mobilization in subcutaneous AT of obese subjects (). At rest and during exercise, plasma noradrenaline and adrenaline concentrations were not different between lean and obese men. During exercise, the exercise-induced increase in extracellular glycerol concentration was 5-6 fold lower in obese than in lean subjects and was strongly enhanced in the obese subjects by addition of an alpha2-AR antogonist. Thus, the physiological stimulation of adipocyte alpha2-ARs during exercice-induced SNS activation contributes to the blunted lipolysis observed in subcutaneous AT of obese men.

In search for novel lipolytic pathways, a putative lipolytic effect of natriuretic peptides in human AT was investigated (). ANP and brain natriuretic peptide (BNP) stimulated lipolysis as much as isoproterenol, a non-selective beta-AR agonist, on isolated human fat cells, whereas C-type natriuretic peptide (CNP) had the lowest lipolytic effect. In situ microdialysis experiments confirmed the potent lipolytic effect of ANP in abdominal subcutaneous AT of healthy subjects. High level of ANP binding sites were found in human adipocytes. The rank order of potency for stimulation of lipolysis (ANP > BNP > CNP) and the existence of an ANP-induced cGMP production sustained the presence of functional type A natriuretic peptide receptor in human fat cells. The data show that natriuretic peptides are novel activators of human AT lipolysis, operating via a cGMP-dependent pathway which does not involve phosphodiesterase inhibition and cAMP production. The lipolytic effect of ANP is increased in parallel to the effect of isoprenaline during a hypocaloric diet (collaboration with V Stich).

In collaboration with Hubert Vidal and Martine Laville (INSERM U449), we have shown that calorie restriction results in an induction of UCP2 and UCP3 mRNAs in skeletal muscle, and of UCP2 mRNA in adipose tissue (). Calorie restriction induces an increase in adipose tissue lipolysis, resulting in an important fatty acid release from body fat stores. A positive relationship was found between UCP3 mRNA expression and plasma FFA level (). Moreover, we showed that fatty acid and PPARgamma ligands are inducers of UCP2 gene expression in human adipocytes ().

Recently, we determined the effect of triiodothyronine (T3) on mRNA levels of UCP and proteins involved in the biogenesis of the respiratory chain (). Young healthy males were treated with T3 for 14 days. The increase in plasma free T3 levels was associated with an increase of resting metabolic rate and a decrease of respiratory quotient. In skeletal muscle, treatment with T3 induced a 2-fold increase of both UCP2 and UCP3 mRNA levels. The mRNA levels of cytochrome c oxidase subunits 2 and 4, nuclear respiratory factor 1, mitochondrial transcription factor A, and the coactivator PGC1 did not change during the treatment. In adipose tissue, UCP2 mRNA levels increased 3-fold. The direct effect of T3 on skeletal muscle and adipose tissue UCP2 and UCP3 mRNA expression was demonstrated in vitro in human primary cultures. Our data show that T3 induces UCP2 and UCP3 mRNA expression in humans. In skeletal muscle, UCP regulation by T3 is not associated with the transcriptional regulation of respiratory chain proteins.