Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse

Abstract

AMPK (adenosine monophosphate-activated protein kinase), a key regulator of cellular energy metabolism and whole-body energy balance, is present in brown adipose tissue but its role in regulating the acute metabolic state and chronic thermogenic potential of this metabolically unique tissue is unknown. To address this, the AMPK signalling system in brown and white adipose tissue was studied in C57Bl/6 mice under control conditions, during acute and chronic cold exposure, and during chronic adrenergic stimulation. In control mice AMPK activity in brown adipose tissue was higher than in any tissue yet reported (3-fold the level in liver) secondary to a high level of expression of the α1 isoform. During the first day of cold, a time of intense non-shivering thermogenesis, AMPK activity remained at basal levels. However, chronic (>7 days) cold caused a progressive increase in brown adipose tissue AMPK activity secondary to increased expression of the α1 isoform. To investigate the signalling pathway involved, noradrenaline (norepinephrine) and the β 3 -adrenergic-specific agonist CL 316, 243 were given for 14 days. This increased uncoupling protein-1 content in brown adipose tissue, but not AMPK activity. In white adipose tissue 15 days of cold increased α1 AMPK activity 98 ± 20%, an effect reproduced by chronic noradrenaline or CL 316 243. We conclude that chronic cold not only increases AMPK activity in brown and white adipose tissue, but that it does so via distinct signalling pathways. Our data are consistent with AMPK acting primarily as a regulator of chronic thermogenic potential in brown adipose tissue, and not in the acute activation of non-shivering thermogenesis.

Cold tolerance, cold-induced hyperphagia, and nonshivering thermogenesis are normal in α1-AMPK−/−mice

“…We previously demonstrated a higher level of ␣ 1 -AMPK activity in BAT than any other tissue in mice (20). In the present study, we confirm this finding and report that chronic loss of ␣ 1 -AMPK from all tissues in the body, including BAT, results in adaptations allowing ␣ 1 -AMPK Ϫ/Ϫ mice to have normal 1) tolerance to chronic cold, 2) hyperphagic response to chronic cold, and 3) acute activation of nonshivering thermogenesis.…”

“…AMPK activity was measured as previously described (20) and expressed as picomoles of phosphate incorporated per minute per milligram of homogenate protein. Briefly, tissue was homogenized in the presence of protease inhibitors and phosphatase inhibitors.…”

“…Previously we reported that BAT in mice contains a higher level of AMP-activated protein kinase (AMPK) expression than any other tissue, including liver, muscle, heart, and white adipose tissue (WAT) (20). Given the established role of AMPK as a "metabolic master switch," in that it helps regulate processes such as food intake, glucose uptake, fatty acid oxidation, mitochondrial biogenesis, protein synthesis, and appetite (12,21,32,36), we hypothesized that AMPK might play a central role in regulating adaptations to chronic cold exposure, cold-induced hyperphagia, and acute nonshivering thermogenesis.…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…AMPK protein amount and activity was found to be two to threefold higher in BAT than in liver (Mulligan et al 2007). Chronic cold exposure of mice led to a progressive increase in AMPK activity in BAT (Mulligan et al 2007) and prolonged lack of adrenergic stimulation led to decreased AMPK activity, which was secondary to reduction in both a1-and a2-AMPK subunits levels (Pulinilkunnil et al 2011).…”

“…AMPK protein amount and activity was found to be two to threefold higher in BAT than in liver (Mulligan et al 2007). Chronic cold exposure of mice led to a progressive increase in AMPK activity in BAT (Mulligan et al 2007) and prolonged lack of adrenergic stimulation led to decreased AMPK activity, which was secondary to reduction in both a1-and a2-AMPK subunits levels (Pulinilkunnil et al 2011). On the other hand, acute blockage of a-adrenergic signaling resulted in stimulation of AMPK activity, mediated by alteration in AMPK a Thr 172 phosphorylation, which could be secondary to diminished oxygen consumption in BAT (Pulinilkunnil et al 2011).…”