Cristina Tonello

Tumor necrosis factor-alpha induces apoptosis in rat brown adipocytes.

Accumulating evidence demonstrates that adipose tissue is a major site of tumor necrosis factor-α (TNF-α) gene expression, which is markedly high in obese animals and may contribute to obesity-linked insulin resistance. We now report that recombinant murine TNF-α triggers the apoptotic degeneration of brown adipocytes differentiated in culture. Moreover, noradrenaline, which has been described as having trophic effects on brown fat and accelerating the differentiation of brown adipocytes, is capable of dose-dependently preventing the TNF-α-induced apoptosis of brown fat cells. Since obesity is characterized by greatly increased TNF-α production and reduced catecholaminergic activity, apoptosis was studied in the brown fat of genetically obese animals. In situ DNA fragmentation analysis revealed a larger number of apoptotic cells in the brown fat of obese (fa/fa) than in that of lean (+/+) Zucker rats. The exposure of obese rats to low temperatures for 7 days, which increases the sympathetic activity of brown adipose tissue, significantly reduces the number of apoptotic brown adipocytes. We hypothesize that TNF-α may play a significant role in the control of brown fat homeostasis.

SR 58611A: A novel thermogenic β-adrenoceptor agonist

Abstract N (2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydropanaphth-2-yl]-(2R)-2-hydroxy-2-(3-chlorophenyl) ethanamine hydrochloride (SR 58611A) increased cyclic AMP levels in membrane homogenates from rat interscapular brown adipose tissue with an EC 50 of 20 ± 2 nM. Substitution of GTP with the GDP analog, guanosine-5− O -[thiodiphosphate], in the incubation medium suppressed the stimulation of adenylyl cyclase activity by SR 58611A. This compound also stimulated glycerol release from the brown fat cells, with an EC 50 of 11 ± 0.4 nM. Only at doses higher than 10 μM did the non-selective β-adrenoceptor antagonist, propranolol and alprenolol, as well as the selective β 1 -andβ 2 -adrenoceptor antagonist, (±)-[2-(3-carbomoyl-4-hydroxyphenoxy ethylaminol]-3[4(1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2 propanol (CGP 20712A) and erythro-(+-)-1-(7- methylindan-4-yloxy)-3-iso-propylaminobutan-2-ol-hydrochloride (ICI 118,551), antagonize the SR 58611A-induced stimulation of both adenylyl cyclase activity and lipid metabolism. Since, at high dose, all these β-adrenoceptor antagonist lack selectivity for β 1 -orβ 2 -adrenoceptors, these results suggest that the β-adrenoceptor agonist, SR 58611A, activates thermogenesis by act on brown fat cell β 3 -adrenoceptors. This implies that this compound might be useful for treatment of obesity.

Tolerance to hypoactivity and sensitization to hyperactivity after chronic treatment with a presynaptic dose of lisuride in rats.

We studied the adaptive changes of the locomotor effects of lisuride, a selective agonist for dopamine (DA) D2 receptors, and the functional state of D1 and D2 receptors after repeated administration of lisuride at a dose supposed to act preferentially on DA autoreceptors. Rats were treated daily with saline or lisuride, at a dose that causes a significant reduction in locomotor activity when given to naive rats (25 micrograms/kg i.p.), for 33 days and the effect of different challenging doses of the drug on locomotor activity was measured at different times during and after the treatment. The functional state of D1 and D2 DA receptors was evaluated by measuring SKF 82526-stimulated and LY 171555-inhibited adenylate cyclase (AC) activity in the caudatus/putamen, nucleus accumbens and substantia nigra and naive and chronically treated rats. There was a progressive decline in the ability of lisuride to decrease locomotor activity in rats given daily injections of lisuride, and there was a marked reduction in the threshold dose of lisuride for causing hypermotility. The functional state of DA receptors, positively or negatively linked to AC activity, was not modified by the treatment. The most suitable explanation of the reported adaptive behavioral changes is a down-regulation of DA autoreceptors after chronic treatment with presynaptic doses of lisuride.