It is well established that catecholamine-stimulated thermogenesis in brown fat requires ␤-adrenergic elevations in cyclic AMP (cAMP) to increase expression of the uncoupling protein 1 (UCP1) gene. However, little is known about the downstream components of the signaling cascade or the relevant transcription factor targets thereof. Here we demonstrate that cAMP-and protein kinase A-dependent activation of p38 mitogenactivated protein kinase (MAPK) in brown adipocytes is an indispensable step in the transcription of the UCP1 gene in mice. By phosphorylating activating transcription factor 2 (ATF-2) and peroxisome proliferatoractivated receptor gamma (PPAR␥) coativator 1␣ (PGC-1␣), members of two distinct nuclear factor families, p38 MAPK controls the expression of the UCP1 gene through their respective interactions with a cAMP response element and a PPAR response element that both reside within a critical enhancer motif of the UCP1 gene. Activation of ATF-2 by p38 MAPK additionally serves as the cAMP sensor that increases expression of the PGC-1␣ gene itself in brown adipose tissue. In conclusion, our findings illustrate that by orchestrating the activity of multiple transcription factors, p38 MAPK is a central mediator of the cAMP signaling mechanism of brown fat that promotes thermogenesis.

Autophagy is essential for maintaining both survival and health of cells. Autophagy is normally suppressed by amino acids and insulin. It is unclear what happens to the autophagy activity in the presence of insulin resistance and hyperinsulinemia. In this study, we examined the autophagy activity in the presence of insulin resistance and hyperinsulinemia and the associated mechanism. Insulin resistance and hyperinsulinemia were induced in mice by a high fat diet, followed by measurements of autophagy markers. Our results show that autophagy was suppressed in the livers of mice with insulin resistance and hyperinsulinemia. Transcript levels of some key autophagy genes were also suppressed in the presence of insulin resistance and hyperinsulinemia. Conversely, autophagy activity was increased in the livers of mice with streptozotocin-induced insulin deficiency. Levels of vps34, atg12, and gabarapl1 transcripts were elevated in the livers of mice with insulin deficiency. To study the mechanism, autophagy was induced by nutrient deprivation or glucagon in cultured hepatocytes in the presence or absence of insulin. Autophagy activity and transcript levels of vps34, atg12, and gabarapl1 genes were reduced by insulin. The effect of insulin was largely prevented by overexpression of the constitutive nuclear form of FoxO1. Importantly, autophagy of mitochondria (mitophagy) in cultured cells was suppressed by insulin in the presence of insulin resistance. Together, our results show that autophagy activity and expression of some key autophagy genes were suppressed in the presence of insulin resistance and hyperinsulinemia. Insulin suppression of autophagy involves FoxO1-mediated transcription of key autophagy genes.Macroautophagy (autophagy) is a catabolic process whereby long lived large molecules and cellular organelles, such as mitochondria and endoplasmic reticulum (ER), 3 are degraded by lysosomes for an alternative energy source during starvation (1, 2). Autophagy is normally activated by glucagon or deprivation of amino acids during starvation (1) but inhibited by amino acids and/or insulin through the mTOR-or/and Akt-dependent pathways after food intake (3, 4). Thus, autophagy activity fluctuates with food intakes and fasts. Importantly, autophagy is also essential for maintaining cellular health by removing misfolded large molecules and aged/dysfunctional cellular organelles, such as mitochondria and ER (1, 5). In other words, decreased autophagy will inevitably slow the removal of misfolded large molecules and aged/dysfunctional cellular organelles. Accumulation of these molecules and dysfunctional cellular organelles may not only contribute to the development of cancers (1) but also contribute to the development of metabolic diseases, such as insulin resistance. For example, the accumulation of dysfunctional mitochondria will most likely cause increased mitochondrion-derived oxidative stress, which is known to contribute to the development of insulin resistance (6 -10).Insulin resistance is either a precursor or...