title: Insulin resistance via modification of PGC1α function identifying a possible preventive role of vitamin D analogues in chronic inflammatory state of obesity. A double blind clinical trial study.
abstract: OBJECTIVE
  Obesity-induced chronic inflammation is a key component of the pathogenesis of insulin resistance. Mounting evidence has demonstrated anti-inflammatory characteristics for vitamin D. Although analogues of vitamin D3 have extensively been used in the treatment of various chronic inflammatory diseases, to our knowledge, no such research is conducted in regards with obesity. The aim of this double blind clinical trial study is to investigate whether alphacalcidol treatment in obese subjects can affect the cytokine profile and insulin resistance. Moreover, we evaluated the pathways of vitamin D receptor (VDR), PPARγ and PGC1α gene expressions which may lead to insulin resistance following treatment with either alphacalcidol or placebo.
  
  
  METHODS
  A total of 94 obese participants (BMI≥30) were recruited for the current double blind clinical trial study. Patients were divided into two intervention (N.=40) and control groups (N.=54) based on the stratified randomized method. One-Alpha® Capsules 1 microgram: alfacalcidol (1-α hydroxyvitamin D3) and placebo were given to subjects once a day for 8 weeks. Analysis of body composition was performed with use of Body Composition Analyzer. The circulating levels of TNF-α, IL-1β, IL-4, IL-6, IL-10, IL-13, IL-17, PTH, and 25-Hydroxy Vi-tamin D were measured with the use of EIA method. The PBMCs were separated from whole blood by Ficoll-hypaque technique. Total cellular RNA was extracted and the cDNA was synthesized. The real-time PCR using specific primer pairs for VDR, PGC1α, PPARγ, and β-actin was performed.
  
  
  RESULTS
  The FPG, fat percent and PTH levels were decreased and the levels of HDL-cholesterol and 25-hydroxy vitamin D were significantly increased after treatment with Alfacalcidol. Regarding to cytokines levels, the levels of IL6 were significantly decreased and IL10 were significantly increased in Alfacalcidol group in comparison with the control group. The relative expressions of VDR, PGC1α, and PPARγ genes significantly increased in Alfacalcidol group. We found also significant positive correlation between circulating 25-OH vitamin D and relative PGC1α gene expression in participants with insulin resistance.
  
  
  CONCLUSIONS
  It seems that Alfacalcidol treatment may be effective in amelioration of the inflammatory state in obesity. This supplement might also improve resistance to insulin through enhancement of relative VDR and its downstream genes expression, which are demonstrated to be involved in glucose homeostasis pathways.
authors.affiliation: Cellular and Molecular Nutrition Department, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran - jalalimahmoud@hotmail.com.
authors.forename: K
authors.initials: K
authors.lastname: Mirzaei
authors.forename: A
authors.initials: A
authors.lastname: Hossein-Nezhad
authors.forename: S A
authors.initials: SA
authors.lastname: Keshavarz
authors.forename: S M
authors.initials: SM
authors.lastname: Eshaghi
authors.forename: F
authors.initials: F
authors.lastname: Koohdani
authors.forename: A A
authors.initials: AA
authors.lastname: Saboor-Yaraghi
authors.forename: S
authors.initials: S
authors.lastname: Hosseini
authors.forename: A
authors.initials: A
authors.lastname: Tootee
authors.forename: M
authors.initials: M
authors.lastname: Djalali
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects; D004311:Double-Blind Method; D005215:Fasting / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D006887:Hydroxycholecalciferols / Q000627:therapeutic use*; D007249:Inflammation / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000032:analysis; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D006887:Hydroxycholecalciferols; D007328:Insulin; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014157:Transcription Factors; C008088:alfacalcidol