title: Parathyroid hormone induces adipocyte lipolysis via PKA-mediated phosphorylation of hormone-sensitive lipase.
abstract: Parathyroid hormone (PTH) is secreted from the parathyroid glands in response to low plasma calcium levels. Besides its classical actions on bone and kidney, PTH may have other important effects, including metabolic effects, as suggested for instance by increased prevalence of insulin resistance and type 2 diabetes in patients with primary hyperparathyroidism. Moreover, secondary hyperparathyroidism may contribute to the metabolic derangements that characterize states of vitamin D deficiency. PTH has been shown to induce adipose tissue lipolysis, but the details of the lipolytic action of PTH have not been described. Here we used primary mouse adipocytes to show that intact PTH (1-84) as well as the N-terminal fragment (1-37) acutely stimulated lipolysis in a dose-dependent manner, whereas the C-terminal fragment (38-84) was without lipolytic effect. The lipolytic action of PTH was paralleled by phosphorylation of known protein kinase A (PKA) substrates, i.e. hormone-sensitive lipase (HSL) and perilipin. The phosphorylation of HSL in response to PTH occurred at the known PKA sites S563 and S660, but not at the non-PKA site S565. PTH-induced lipolysis, as well as phosphorylation of HSL at S563 and S660, was blocked by both the PKA-inhibitor H89 and the adenylate cyclase inhibitor MDL-12330A, whereas inhibitors of extracellular-regulated kinase (ERK), protein kinase B (PKB), AMP-activated protein kinase (AMPK) and Ca(2+)/calmodulin-dependent protein kinase (CaMK) had little or no effect. Inhibition of phosphodiesterase 4 (PDE4) strongly potentiated the lipolytic action of PTH, whereas inhibition of PDE3 had no effect. Our results show that the lipolytic action of PTH is mediated by the PKA signaling pathway with no or minor contribution of other signaling pathways and, furthermore, that the lipolytic action of PTH is limited by simultaneous activation of PDE4. Knowledge of the signaling pathways involved in the lipolytic action of PTH is important for our understanding of how metabolic derangements develop in states of hyperparathyroidism, including vitamin D deficiency.
authors.affiliation: Section for Diabetes, Metabolism and Endocrinology, Department of Experimental Medical Science, Lund University, BMC C11, 221 84 Lund, Sweden. Electronic address: sara.larsson@med.lu.se.
authors.forename: Sara
authors.initials: S
authors.lastname: Larsson
authors.affiliation: Section for Diabetes, Metabolism and Endocrinology, Department of Experimental Medical Science, Lund University, BMC C11, 221 84 Lund, Sweden. Electronic address: helena.jones@med.lu.se.
authors.forename: Helena A
authors.initials: HA
authors.lastname: Jones
authors.affiliation: Section for Diabetes, Metabolism and Endocrinology, Department of Experimental Medical Science, Lund University, BMC C11, 221 84 Lund, Sweden. Electronic address: olga.goransson@med.lu.se.
authors.forename: Olga
authors.initials: O
authors.lastname: Göransson
authors.affiliation: Section for Diabetes, Metabolism and Endocrinology, Department of Experimental Medical Science, Lund University, BMC C11, 221 84 Lund, Sweden. Electronic address: eva.degerman@med.lu.se.
authors.forename: Eva
authors.initials: E
authors.lastname: Degerman
authors.affiliation: Section for Diabetes, Metabolism and Endocrinology, Department of Experimental Medical Science, Lund University, BMC C11, 221 84 Lund, Sweden. Electronic address: cecilia.holm@med.lu.se.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Holm
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors / Q000494:pharmacology; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007097:Imines / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D000070778:Perilipin-1; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism; D044183:Receptor, Parathyroid Hormone, Type 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D002787:Sterol Esterase / Q000378:metabolism*
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D002352:Carrier Proteins; D007097:Imines; C473449:PTH1R protein, human; D010281:Parathyroid Hormone; D000070778:Perilipin-1; D058988:Phosphodiesterase 4 Inhibitors; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D044168:Receptor, Parathyroid Hormone, Type 1; D044183:Receptor, Parathyroid Hormone, Type 2; C014925:RMI 12330A; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002787:Sterol Esterase; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: Adipocyte; Lipolysis; PDE; PKA; PTH; cAMP