title: Differences in adiposity in Cushing syndrome caused by PRKAR1A mutations: clues for the role of cyclic AMP signaling in obesity and diagnostic implications.
abstract: BACKGROUND
  The cAMP signaling pathway is implicated in bilateral adrenocortical hyperplasias. Bilateral adrenocortical hyperplasia is often associated with ACTH-independent Cushing syndrome (CS) and may be caused by mutations in genes such as PRKAR1A, which is responsible for primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A regulates cAMP-dependent protein kinase (PKA), an essential enzyme in the regulation of adiposity. Although CS is invariably associated with obesity, its different forms, including those associated with PKA defects, have not been compared.
  
  
  OBJECTIVE
  The purpose of this study was to characterize the phenotypic and molecular differences in periadrenal adipose tissue (PAT) between patients with CS with and without PRKAR1A mutations.
  
  
  METHODS
  Samples from adrenalectomies of 51 patients were studied: patients with CS with (n = 13) and without (n = 32) PRKAR1A mutations and a comparison group with aldosterone-producing adenomas (APAs) (n = 6). In addition, clinical data from a larger group of patients with Cushing disease (n = 89) and hyperaldosteronism (n = 26) were used for comparison.
  
  
  METHODS
  Body mass index (BMI), abdominal computed tomography scans, and cortisol data were collected preoperatively. PAT was assayed for PKA activity, cAMP levels, and PKA subunit expression.
  
  
  RESULTS
  BMI was lower in adult patients with CS with PRKAR1A mutations. cAMP and active PKA levels in PAT were elevated in patients with CS with PRKAR1A mutations.
  
  
  CONCLUSIONS
  Increased PKA signaling in PAT was associated with lower BMI in CS. Differences in fat distribution may contribute to phenotypic differences between patients with CS with and without PRKAR1A mutations. The observed differences are in agreement with the known roles of cAMP signaling in regulating adiposity, but this is the first time that germline defects of PKA are linked to variable obesity phenotypes in humans.
authors.affiliation: Section on Endocrinology and Genetics (E.L., A.R., M.L., E.G., M.K., C.L., M.d.l.L.S., M.N., C.A.S.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Inter-Institute Pediatric Endocrinology Training Program (E.G.), and Department of Diagnostic Radiology (N.P., C.A.S.), Clinical Research Center, National Institutes of Health, Bethesda, Maryland 20892; and Service d'Endocrinologie Pédiatrique (A.R.), Université Paris-Sud 11, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France.
authors.forename: Edra
authors.initials: E
authors.lastname: London
authors.forename: Anya
authors.initials: A
authors.lastname: Rothenbuhler
authors.forename: Maya
authors.initials: M
authors.lastname: Lodish
authors.forename: Evgenia
authors.initials: E
authors.lastname: Gourgari
authors.forename: Meg
authors.initials: M
authors.lastname: Keil
authors.forename: Charalampos
authors.initials: C
authors.lastname: Lyssikatos
authors.forename: Maria
authors.initials: M
authors.lastname: de la Luz Sierra
authors.forename: Nicolas
authors.initials: N
authors.lastname: Patronas
authors.forename: Maria
authors.initials: M
authors.lastname: Nesterova
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D003480:Cushing Syndrome / Q000235:genetics* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D000242:Cyclic AMP