Association of Type 2 Deiodinase Thr92Ala Polymorphism with Pediatric Obesity in Japanese Children: A Case-Control Study

Genetic factors play critical roles in the onset and progression of obesity. Brown adipose tissue (BAT) activity is also critical for adiposity. The objective of this study was to evaluate the prevalence and effects of BAT gene polymorphisms in pediatric obesity. This case-control study included 270 non-obese and 86 obese children. All participants underwent genotyping for type 2 deiodinase (DIO2) Thr92Ala (rs225014). The prevalence of the homozygous Ala/Ala allele of the DIO2 gene in the obese group was 15.1% versus 6.3% in the non-obese group, resulting in an odds ratio (OR) of 3.393 (p = 0.003). The results of this study indicate that the homozygous Ala/Ala allele of the DIO2 gene is associated with an increased risk of pediatric obesity and suggest that pediatric obesity might be suitable for assessing the association with gene polymorphisms related to BAT, especially DIO2 Thr92Ala

Erythropoietin (EPO) ameliorates obesity and glucose homeostasis by promoting thermogenesis and endocrine function of classical brown adipose tissue (BAT) in diet-induced obese mice

<div><p>Erythropoietin (EPO), clinically used as a hematopoietic drug, has received much attention due to its nonhematopoietic effects. EPO reportedly has beneficial effects on obesity and diabetes mellitus. We investigated whether interscapular brown adipose tissue (iBAT: main part of classical BAT) could play a role in EPO’s anti-obesity and anti-diabetic effects in diet-induced obese mice. Four-week-old male C57BL/6J mice were fed a high-fat diet (HFD-Con), and half were additionally given an intraperitoneal injection of recombinant human EPO (200 IU/kg) (HFD-EPO) thrice a week for four weeks. At 8 weeks, EPO-injected mice showed significantly reduced body weight with reduced epididymal and subcutaneous white fat mass and unchanged caloric intake and locomotor activity. HOMA-IR (insulin resistance index) and glucose levels during intraperitoneal glucose tolerance test (IPGTT) were significantly lower in HFD-EPO mice than in HFD-Con mice. EPO-injected mice also showed increased oxygen consumption, indicative of metabolic rate, and skin temperature around iBAT tissue masses. EPO significantly upregulated the PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16), a transcriptional factor with a crucial role in brown adipocyte differentiation. EPO significantly increased phosphorylated signal transducer and activator of transcription 3 (STAT3), which is downstream of erythropoietin receptor (EpoR) and known to stabilize PRDM16. EPO’s suppression of myocyte enhancer factor 2c (Mef2c) and microRNA-133a (miR-133a) via β3-adrenergic receptor caused PRDM16 upregulation. EPO-mediated enhancement of EpoR/STAT3 and β-adrenergic receptor/Mef2c/miR-133 pathways dramatically increases total uncoupling protein 1 (UCP1), an essential enzyme for BAT thermogenesis. Furthermore, EPO activated BAT’s endocrine functions. EPO facilitated fibroblast growth factor 21 (FGF21) production and excretion in iBAT, associated with reduction of liver gluconeogenesis-related genes. Thus, EPO’s improvement of obesity and glucose homeostasis can be attributed to increased iBAT thermogenic capacity and activation of BAT’s endocrine functions.</p></div

Effect of erythropoietin (EPO) on body weight gain.

<p><b>(A)</b> Change in body weight. <b>(B)</b> Weekly food intake. <b>(C)</b> Total food intake. (<b>D)</b> Locomotor activity. Values are mean ± SE for 5–10 mice. ^a<i>P</i> < 0.05 or ^aa<i>P</i> < 0.01, vs. mice fed normal chow diet (NC-Con). ^bP < 0.05 or ^bbP < 0.01, vs. mice fed normal chow diet plus EPO (NC-EPO). ^cP < 0.05 or ^ccP < 0.01, vs. mice fed high-fat diet alone (HFD-Con).</p

Effect of erythropoietin (EPO) on EpoR/STAT3 axis in interscapular BAT.

<p><b>(A)</b> Western blot analysis. <b>(B)</b> <i>p</i>EpoR/EpoR and <i>p</i>STAT3/STAT3 ratios were calculated. Values given are mean ± SE for 6 mice. ^a<i>P</i> < 0.05 or ^aa<i>P</i> < 0.01, vs. mice fed normal chow diet (NC-Con). ^bP < 0.05 or ^bbP < 0.01, vs. mice fed normal chow diet plus EPO (NC-EPO). ^cP < 0.05 or ^ccP < 0.01, vs. mice fed high-fat diet alone (HFD-Con).</p

Effect of erythropoietin (EPO) on expression/secretion of FGF21 in interscapular BAT (iBAT) and the liver and gluconeogenesis-related genes in the liver.

<p><b>(A)</b> Real-time PCR experiments in iBAT. <b>(B)</b> Western blot analysis. (<b>C)</b> Real-time PCR experiments in liver tissue. (<b>D)</b> Plasma levels of FGF21. <b>(E)</b> Real-time PCR experiments in liver tissue. Values given are mean ± SE for 3–8 mice. ^a<i>P</i> < 0.05 or ^aa<i>P</i> < 0.01, vs. mice fed normal chow diet (NC-Con). ^bP < 0.05 or ^bbP < 0.01, vs. mice fed normal chow diet plus EPO (NC-EPO). ^cP < 0.05 or ^ccP < 0.01, vs. mice fed a high-fat diet alone (HFD-Con).</p

Effect of erythropoietin (EPO) on differentiation-, lipolysis- and thermogenesis-related genes in white adipose tissue (WAT).

<p><b>(A)</b> Real-time PCR experiments in subcutaneous WAT (sWAT). <b>(B)</b> Real-time PCR experiments in epididymal WAT (eWAT). Values given are mean ± SE for 4–8 mice. ^a<i>P</i> < 0.05 or ^aa<i>P</i> < 0.01, vs. mice fed normal chow diet (NC-Con). ^bP < 0.05 or ^bbP < 0.01, vs. mice fed normal chow diet plus EPO (NC-EPO). ^cP < 0.05 or ^ccP < 0.01, vs. mice fed high-fat diet alone (HFD-Con).</p