title: Four novel UCP3 gene variants associated with childhood obesity: effect on fatty acid oxidation and on prevention of triglyceride storage.
abstract: OBJECTIVE
  The objective of the study was to look for uncoupling protein 3 (UCP3) gene variants in early-onset severe childhood obesity and to determine their effect on long-chain fatty acid oxidation and triglyceride storage.
  
  
  RESULTS
  We identified four novel mutations in the UCP3 gene (V56M, A111V, V192I and Q252X) in 200 children with severe, early-onset obesity (body mass index-standard deviation score >2.5; onset: <4 years) living in Southern Italy. We evaluated the role of wild-type (wt) and mutant UCP3 proteins in palmitate oxidation and in triglyceride storage in human embryonic kidney cells (HEK293). Palmitate oxidation was ∼60% lower (P<0.05; P<0.01) and triglyceride storage was higher in HEK293 cells expressing the four UCP3 mutants than in cells expressing wt UCP3. Moreover, mutants V56M and Q252X exerted a dominant-negative effect on wt protein activity (P<0.01 and P<0.05, respectively). Telmisartan, an angiotensin II receptor antagonist used in the management of hypertension, significantly (P<0.05) increased palmitate oxidation in HEK293 cells expressing wt and mutant proteins (P<0.05; P<0.01), including the dominant-negative mutants.
  
  
  CONCLUSIONS
  These data indicate that protein UCP3 affects long-chain fatty acid metabolism and can prevent cytosolic triglyceride storage. Our results also suggest that telmisartan, which increases fatty acid oxidation in rat skeletal muscle, also improves UCP3 wt and mutant protein activity, including the dominant-negative UCP3 mutants.
authors.affiliation: Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.
authors.forename: C V
authors.initials: CV
authors.lastname: Musa
authors.forename: A
authors.initials: A
authors.lastname: Mancini
authors.forename: A
authors.initials: A
authors.lastname: Alfieri
authors.forename: G
authors.initials: G
authors.lastname: Labruna
authors.forename: G
authors.initials: G
authors.lastname: Valerio
authors.forename: A
authors.initials: A
authors.lastname: Franzese
authors.forename: F
authors.initials: F
authors.lastname: Pasanisi
authors.forename: M R
authors.initials: MR
authors.lastname: Licenziati
authors.forename: L
authors.initials: L
authors.lastname: Sacchetti
authors.forename: P
authors.initials: P
authors.lastname: Buono
mesh_terms: D017668:Age of Onset; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D057809:HEK293 Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007473:Ion Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007558:Italy / Q000453:epidemiology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D000077333:Telmisartan; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*; D000071247:Uncoupling Protein 3
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D014280:Triglycerides; C000604392:UCP3 protein, human; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D000077333:Telmisartan