Metabolism in Cancer

We have established and molecularly mapped the close interaction of a nuclear hormone receptor, namely the glucocorticoid receptor (GR), with hepatic STAT5 that is largely but not exclusively triggered by hepatic activation of JAK2 kinase. Disruption of the GR-JAK2-STAT5 signaling axis causes metabolic syndrome with aggressive liver cancer development in the case of GR/STAT5 deletion but surprisingly not in the case of JAK2 deletion. The RM lab is currently pioneering work into how lipolysis is regulated by GR-STAT5 action. Many cancer patients suffer from a progressive weight loss, called cachexia. Cancer cachexia is characterized by atrophy of adipose tissues and skeletal muscle, resulting in reduced quality of life, and a shortened survival time. Mobilization of adipose tissue in cancer patients is due to an increased lipolysis induced by tumor or host signaling molecules. Glucocorticoids (GC) have been hypothesized as potential mediators of cancer cachexia, as plasma levels of the prolipolytic steroid hormone are elevated in cachectic patients compared to those without cachexia. For this study we genetically introduce disturbances of the GR-JAK2-STAT5 signaling axis, since we have shown previously that it causes metabolic syndrome and peripheral lipolysis. Thus, we deleted the GR or STAT5 from fat tissues. We confirmed in preliminary experiments that peripheral fat depots cannot be mobilized under physiologic challenge.

Glucocorticoid Receptor Signaling Drives Lipolysis: A H&E staining of epididymal white adipose tissue (EWAT) and plasma non-esterified fatty acids (NEFA) of fasted mice reveals reduced lipid mobilization in GR-deficient animals. B Western blot displaying decreased fasting-induced protein kinase A (PKA) activity in EWAT from fasted GR-deficient mice. Western blot against phosphorylated PKA substrates containing a RRX(S*/T*) epitope motif. C Ex vivo analysis of lipolysis and cAMP production in EWAT explants displaying that lipolysis is impaired in GR-deficient EWAT upon β-adrenergic receptor (βAR) activation but not in response to direct adenylate cyclase agonism. Explants were treated with isoproterenol (Iso, non-selective β-adrenergic agonist), CL-316,243 (CL, selective β3-adrenergic agonist) or forskolin (Forsk, adenylate cyclase agonist) to engage signaling steps distal to βAR activation. For A and C: Data are shown as the mean ±SEM; *P < 0.05; ** P < 0.01; *** P < 0.001. D Proposed model for GR-dependent regulation of the lipolytic cascade. Stimulation of βARs (innervation and catecholamines) results in activation of heterotrimeric G proteins and adenylate cyclase. These signaling events stimulate the production of cAMP, subsequent activation of PKA and the induction of lipolysis. PKA phosphorylates and activates HSL in addition to perilipin 1 (PLIN1), which associates with the cytoplasmic side of the lipid vacuoles. Under basal conditions, perilipin 1 sequesters the ATGL co-activator CGI58. PKA-mediated phosphorylation of perilipin 1 results in the release of CGI58, its subsequent association with and activation of ATGL. The GR is required for full lipolytic capacity under fasting conditions by by enhancing the signal transduction from βARs to adenylate cylases.
Glucocorticoid Receptor Signaling Drives Lipolysis 1