brl-37344 and Body-Weight

Cold exposure and a variety of types of mild stress increase pain in patients with painful disorders such as fibromyalgia syndrome. Acutely, stress induces thermogenesis by increasing sympathetic activation of beta-3 (β3) adrenergic receptors in brown adipose tissue. Chronic stress leads to the hypertrophy of brown adipose, a phenomenon termed adaptive thermogenesis. Based on the innervation of skeletal muscle by collaterals of nerves projecting to brown adipose, we theorized an association between brown adipose tissue activity and musculoskeletal hyperalgesia and tested this hypothesis in mice. Exposure to a cold swim or injection of BRL37344 (β3 adrenergic agonist) each enhanced musculoskeletal hyperalgesia, as indicated by morphine-sensitive decreases in grip force responses, whereas SR59230A (β3 adrenergic antagonist) attenuated swim-induced hyperalgesia. Chemical ablation of interscapular brown adipose, using Rose Bengal, attenuated the development of hyperalgesia in response to either swim stress or BRL37344. In addition, elimination of the gene expressing uncoupling protein-1 (UCP1), the enzyme responsible for thermogenesis, prevented musculoskeletal hyperalgesia in response to either a swim or BRL37344, as documented in UCP1-knockout (UCP1-KO) mice compared with wild-type controls. Together, these data provide a convergence of evidence suggesting that activation of brown adipose contributes to stress-induced musculoskeletal hyperalgesia.

Topics: Adipose Tissue, Brown; Adrenergic beta-Agonists; Animals; Body Temperature; Body Weight; Cold Temperature; Disease Models, Animal; Ethanolamines; Female; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Strength; Musculoskeletal Pain; Pain Threshold; Reaction Time; Swimming; Tail; Uncoupling Protein 1

We analysed the sensitivity to beta-adrenoceptor agonists in epididymal adipose cells from rats submitted to a stress protocol previously reported to induce alterations in sensitivity to catecholamines in cardiac tissue from rats. Food intake and body weight were lower, whereas adipocytes basal lipolysis was higher (control: 0.59 +/- 0.04; stress: 1.00 +/- 0.11, micromol glycerol/100 mg total lipids/100 min) in stressed compared to control rats. The responses to isoprenaline (pD(2) control: 7.46 +/- 0.11; stress: 8.11 +/- 0.17), adrenaline (pD(2) control: 5.78 +/- 0. 20; stress: 6.13 +/- 0.18), and salbutamol (pD(2) control: 5.64 +/- 0.28; stress: 5.92 +/- 0.34) were sensitized, and the lipolytic responses to norepinephrine (pD(2) control: 6.98 +/- 0.13; stress: 6. 41 +/- 0.12) and to BRL37344 (pD(2) control: 8.43 +/- 0.19; stress: 7.54 +/- 0.21) were desensitized. Responses to the higher concentration (100 microm) of isoprenaline (control: 1.80 +/- 0.18; stress: 2.24 +/- 0.10 micromol glycerol/100 mg total lipids/100 min), epinephrine (control: 1.64 +/- 0.17; stress: 2.24 +/- 0.14 micromol glycerol/100 mg total lipids/100 min), salbutamol (control: 0.65 +/- 0.11; stress: 1.21 +/- 0.41 micromol glycerol/100 mg total lipids/100 min), and d-butyryl-cAMP (control: 1.59 +/- 0.17; stress: 2.72 +/- 0.25) were significantly enhanced in adipocytes from stressed rats. pD(2) or maximum response to CGP12177 were not altered. Supersensitivity to isoprenaline was abolished by 50 nm ICI118,551 but was not modified by 100 nm metoprolol. However, subsensitivity to norepinephrine and to BRL37344 was abolished by 100 nM metoprolol. Our results suggest that in epididymal adipocytes from stressed rats there is a desensitization of the response to adrenoceptor agonists mediated by beta(1)-adrenoceptors together with a sensitization of the response mediated by beta(2)-adrenoceptors. beta(3)-adrenoceptors seem to be resistant to the stress effect.

Topics: Adipose Tissue; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Albuterol; Animals; Body Weight; Bucladesine; Eating; Epinephrine; Ethanolamines; Glycerol; Isoproterenol; Lipolysis; Male; Metoprolol; Norepinephrine; Propanolamines; Rats; Rats, Wistar; Stress, Physiological

Variations in total energy intake and composition of daily food play an important role in the regulation of metabolic processes and so, in the control of body weight. This study was designed in order to investigate the effect of a high-fat diet on lipolysis in isolated adipocytes. For this purpose, fourteen Wistar rats were divided into two groups and fed either a standard-fat diet or a high-fat diet ad libitum for 7 weeks. Adipocytes were prepared from fat pads by collagenase digestion and incubated in vitro in the absence or presence of various lipolytic agents. Lipolysis was measured by the release of glycerol into the medium during 90 min of incubation. We observed that a high amount of fat in the diet induced an enlargement of adipose tissue, which was accompanied by a reduction of beta-adrenergic agonist-induced lipolysis, that could be due to a loss of beta(1) and beta(3)-adrenoceptor number or to alterations of their coupling to adenylate-cyclase through the guanine nucleotide regulatory protein. New data about regional differences were provided by comparing two adipose locations (subcutaneous and visceral).

Topics: Adipocytes; Adipose Tissue; Adrenergic beta-Agonists; Animals; Body Weight; Bucladesine; Colforsin; Cyclic AMP; Diet, Atherogenic; Dietary Fats; Dobutamine; Eating; Ethanolamines; Fatty Acids, Nonesterified; Female; Glycerol; Lipolysis; Rats; Rats, Wistar

The beta-adrenergic effects of catecholamines are potentiated by thyroid hormones in adipose tissue. Amiodarone (AM) is structurally similar to thyroid hormones and was used to explore the mechanism of the triiodothyronine (T3) effect on beta-adrenergic receptors (beta-ARs) in adipose tissue. AM decreases the expression of some T3 sensitive genes in various tissues and antagonizes the effect of T3 on its nuclear receptors. In this study, the T3, AM and AM + T3 effects on the beta 1- and beta 3-AR density were assessed on rat white adipocytes by radioligand binding using [3H]CGP 12177 after characterization of these subtypes by displacement of [3H]CGP 12177 binding by isoproterenol, BRL 37344 and noradrenaline. BRL 37344 was used to study beta 3-AR lipolysis. White adipocytes from hyperthyroid rats had increased responsiveness (Emax x 2) and sensitivity (+ 38%) to BRL 37344, while those given AM alone had decreased values. Moreover, AM antagonized the T3 effect on lipolysis. The beta 1-binding characteristics (receptor density [Bmax]: 45 +/- 4 fmol/mg of proteins; dissociation factor [Kd]: 0.96 +/- 0.10 nM) were not modified by either compound. Finally, T3 significantly increased beta 3-AR density (587 +/- 69 versus 363 +/- 25 fmol/mg of proteins) and Kd (38 +/- 2 versus 23 +/- 3 nM), while AM alone had no effect and did not antagonize the T3 effect on beta 3-AR number. In conclusion, the hyperthyroid state in the rat potentiated the lipolytic response of white adipocytes to a specific beta 3-agonist and increased the beta 3-AR density without changing in beta 1-AR number and affinity. Furthermore, the lack of antagonism between AM and T3 on beta 3-AR expression suggests that T3 does not work directly on the beta 3-AR gene. Moreover, AM induced a functional tissular hypothyroid-like effect and its antilipolytic effect probably occurred at a postreceptor level.

Topics: Adipocytes; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Amiodarone; Analysis of Variance; Animals; Anti-Arrhythmia Agents; Body Weight; Dose-Response Relationship, Drug; Ethanolamines; Lipolysis; Male; Propanolamines; Rats; Rats, Wistar; Receptors, Adrenergic, beta; Triiodothyronine