Comprehensive analysis of the effect of genetic variation on white adipose tissue browning

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17976
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Hiraike Yuta 東京大学, 保健・健康推進本部, 助教 (30813935)
• Project Period (FY): 2021-03-01 – 2023-03-31
• Keywords: 褐色脂肪細胞 / 遺伝子多型 / ゲノム-エピゲノム連関 / 肥満症

Outline of Final Research Achievements

Thermogenic brown and beige adipocytes counteract obesity by enhancing energy dissipation via mitochondrial Ucp1. However, the effect of genetic variation on these cells, a major source of disease susceptibility, has been less well studied. Here we comprehensively analyzed the effect of genetic variation on adipocyte browning using obesity-prone C57BL/6J mice, obesity-resistant 129X1/SvJ mice, and F1 offspring of these two strains as a model system. We identified a cis-regulatory variant, rs47238345, at the Ucp1 -12kb enhancer that is responsible for differential Ucp1 expression through allele-specific binding analysis of nuclear factor I-A (NFIA). We also identified Lim homeobox protein 8 (Lhx8), whose expression is higher in 129 than in B6, as a trans-acting positive regulator of Ucp1 expression.These results demonstrate the cis- and trans-acting effects of genetic variation on Ucp1 expression that underlie phenotypic diversity.

Free Research Field

脂肪細胞の生物学

Academic Significance and Societal Importance of the Research Achievements

現存する肥満症の薬物治療および外科治療は「エネルギー摂取の抑制」という考え方に基づいている。腸管や中枢神経系に作用して脂肪の吸収を阻害したり食欲を抑制したりする薬剤は現存するが、副作用等の懸念から実臨床では十分には活用されていない。高度肥満症例に対する外科手術の有効性は確立されつつあるが、適応が限られることは明らかである。本研究を発展させることによりゲノム多型がヒト褐色脂肪細胞の活性を制御するメカニズムが解明され、更にそのようなゲノム多型が褐色脂肪細胞の機能を介して臨床転帰に与える影響が明らかになれば、「エネルギー消費の促進」に基づく肥満症の精密医療に結実することが期待される。