Ambient Temperature Regulation of Apoptosis in Brown Adipose Tissue

Abstract

Brown adipose tissue hyperplasia is a fundamental response to low ambient temperature. We show here that cold exposure of an animal markedly increased the phosphorylation of mitogen-activated protein kinase (p42/p44) Erk1 and Erk2 in brown adipose tissue, and protected cells in the tissue from apoptosis. We also show that cessation of the sympathetic stimulus, by transferring cold-adapted animals to 28°C, caused an increased rate of apoptosis in the tissue. In primary cultures of brown adipose tissue, norepinephrine (NE) stimulated both the phosphorylation and the activity of Erk1/2 via the Erk kinase MEK, and protected the cells form apoptosis. Similarly, agonist stimulation of ␣ 1 -and ␤-adrenergic receptors and increases in the intracellular level of Ca 2؉ and cAMP stimulated the phosphorylation of Erk1/2. Agonist stimulation of ␣ 1 -and ␤-adrenergic receptors, and increased intracellular cAMP level also promoted the cell survival. Furthermore, NE stimulated the expression and secretion of basic fibroblast growth factor (bFGF), which further promoted the cell survival via MEK-dependent activation of Erk1/2. In essence, we show that Erk1/2 has a critical role in promoting NE-and bFGF-dependent survival of brown adipocytes, and propose that NE-and bFGF-dependent regulation of the cell survival is involved in the coldinduced hyperplasia of brown adipose tissue.

β3- and α1-Adrenergic Erk1/2 Activation Is Src- but Not Gi-mediated in Brown Adipocytes

“…On day 4, the medium was changed to one without serum, consisting of Dulbecco's modified Eagle's medium/Ham's F12 (1:1 mixture, Life Technologies, Inc.) supplemented with 0.5% (w/v) fatty acid-free bovine serum albumin (fraction V, Roche Molecular Biochemicals), 2.4 nM insulin, 25 g/ml sodium ascorbate, 10 mM Hepes, 4 mM L-glutamine, 50 IU/ml penicilin, and 50 g/ml streptomycin. The cells were incubated in this medium for 24 h to reduce basal Erk1/2 activity before experiments (15).…”

“…Brown Adipocytes-Norepinephrine activates Erk1/2 in brown adipocytes (14,15). To delineate in detail which adrenergic receptor subtype(s) mediates the norepinephrine effect, we stimulated brown adipocytes with different adrenergic agonists.…”

“…cAMP accumulation (11)(12)(13). Furthermore, in these cells, adrenergic stimulation has already been demonstrated to lead to an activation of Erk1/2 (14,15), which has been shown to be of high physiological significance, as it is linked to inhibition of apoptosis (15). We therefore consider this an optimal system in which to elucidate the physiological significance of the proposed novel ␤ 3 /G i pathway for Erk1/2 activation.…”

Adipose tissue cellularity and apoptosis after intracerebroventricular injections of leptin and 21 days of recovery in rats

“…27 Increasing sympathetic output to BAT by exposure to low temperature increased the Bcl-2/Bax protein ratio 26 and reduced apoptotic cell death of brown adipocytes. [47][48][49] This was also mimicked by the addition of noradrenaline to brown adipocytes in culture. 26,49 The present study similarly suggests that leptin administration increases signals, such as sympathetic outflow, to the RP and EPI white fat pads and BAT to upregulate UCP and/or the Bcl-2/Bax ratio in these tissues.…”

“…[47][48][49] This was also mimicked by the addition of noradrenaline to brown adipocytes in culture. 26,49 The present study similarly suggests that leptin administration increases signals, such as sympathetic outflow, to the RP and EPI white fat pads and BAT to upregulate UCP and/or the Bcl-2/Bax ratio in these tissues. Bcl-2 may function to maintain mitochondrial stability allowing uncoupling proteins to defend against leptin-induced ROS production.…”