Catecholamine-induced lipolysis causes mTOR complex dissociation and inhibits glucose uptake in adipocytes

Abstract

Anabolic and catabolic signaling oppose one another in adipose tissue to maintain cellular and organismal homeostasis, but these pathways are often dysregulated in metabolic disorders. Although it has long been established that stimulation of the β-adrenergic receptor inhibits insulin-stimulated glucose uptake in adipocytes, the mechanism has remained unclear. Here we report that β-adrenergic-mediated inhibition of glucose uptake requires lipolysis. We also show that lipolysis suppresses glucose uptake by inhibiting the mammalian target of rapamycin (mTOR) complexes 1 and 2 through complex dissociation. In addition, we show that products of lipolysis inhibit mTOR through complex dissociation in vitro. These findings reveal a previously unrecognized intracellular signaling mechanism whereby lipolysis blocks the phosphoinositide 3-kinase-Akt-mTOR pathway, resulting in decreased glucose uptake. This previously unidentified mechanism of mTOR regulation likely contributes to the development of insulin resistance.A dipose tissue plays an essential role in maintaining wholebody energy homeostasis by storing or releasing nutrients. This balance is controlled by opposing signaling pathways where anabolic processes are activated by insulin (INS) and catabolic actions are activated by catecholamines. An important unanswered question in adipose biology is how catecholamine-induced β-adrenergic signaling opposes insulin-stimulated glucose uptake (1-6). Surprisingly, the underlying mechanism for this wellestablished physiological response in adipocytes is still unknown.When nutrients are plentiful, insulin is released by the pancreas and stimulates the absorption of glucose and fatty acids in adipose tissue, where they are packaged and stored as triacylglycerol (TAG) in cellular lipid droplets. Insulin signaling in adipocytes is mediated by the phosphoinositide 3-kinase (PI3K)-Akt-mTOR pathway. mTOR is a highly conserved serine/threonine protein kinase that functions in either of two distinct multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is defined primarily by the association of mTOR with raptor, whereas mTORC2 includes mTOR with rictor (7). Importantly, mTORC2 phosphorylation of Akt at S473 is required for Akt activity on AS160, which is necessary for glucose uptake in response to insulin (8-11). Of note, for both mTORC1 and mTORC2, the integrity of these protein complexes is essential for kinase substrate specificity and proper signaling (12, 13).During periods of fasting or stress, catecholamines are released by the sympathetic nervous system to activate lipolysis. Stimulation of the β-adrenergic receptor on adipocytes activates adenylyl cyclase (AC), leading to elevated cAMP and protein kinase A (PKA) activity. PKA initiates lipolysis by direct phosphorylation of hormone-sensitive lipase (HSL) and perilipin (14-16) and indirect activation of adipose triglyceride lipase (ATGL) (17-19). Lipolysis involves hydrolysis of TAG stored in the lipid droplet to produce diacylglycerol (DAG), mo...

The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging

“…mTORC2 activity in hepatocytes is inhibited by overexpression of glycerol-3-phosphate acyltransferase-1 (Gpat1), and mTORC2 can be disrupted in vitro by treatment with preferred Gpat1 substrates (Zhang et al, 2012). Similar recent studies have found that lipolytic products produced either in vivo or in vitro can disrupt mTORC2, although the precise lipid or lipids that mediate this effect have not been identified (Mullins et al, 2014). Conversely, mTORC2 activity can be stimulated by expression of fatty acid elongase-5 (Elovl5), or by treatment of cells with the Elovl5 substrate palmitoleic acid (Tripathy and Jump, 2013).…”

Brown Adipose Tissue Activation Is Linked to Distinct Systemic Effects on Lipid Metabolism in Humans

“…Thyroid hormones and leptin can improve insulin sensitivity (Lin et al, 2002; Lin and Sun, 2011; Petersen et al, 2002; Sivitz et al, 1997), and they have been linked with increased BAT activity (Chondronikola et al, 2014; Collins et al, 1996). These results suggest that BAT activation may (directly or indirectly) abolish the negative effect of cold-induced increase in catecholamines in adipose tissue insulin sensitivity (Mullins et al, 2014). …”

Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue

“…For example, cAMP promotes mTORC1 activity in thyroid cells (39) and β-cells (40), whereas it disrupts both mTORC1 and mTORC2 in MEFs (41) and, via the downstream effects on lipolysis, in white adipocytes (42). In brown adipocytes, β-adrenergic signaling promotes translocation of GLUT1 to the plasma membrane in an mTORC2-dependent, but cAMP-independent, manner, whereas in muscle cells, β-adrenergic signaling activates mTORC2 via PKA.…”