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A newly identified compound activating UCP1 inhibits obesity and its related metabolic disorders

Ken Onodera1, Yutaka Hasegawa1, Nozomi Yokota1

  • 1Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan.

Obesity (Silver Spring, Md.)
|November 17, 2023
PubMed
Abstract

Insights

Researchers discovered a compound that boosts thermogenesis in fat cells, aiding weight management and improving metabolic health. This compound also identified two new genes crucial for energy expenditure.

Area of Science:

  • Metabolic Research
  • Obesity Therapeutics
  • Adipose Tissue Biology

Background:

  • Thermogenesis in adipose tissue is a key strategy for combating obesity and metabolic dysfunction.
  • Identifying novel compounds that activate thermogenic pathways is crucial for developing effective treatments.

Purpose of the Study:

  • To screen for compounds that promote thermogenesis in adipocytes.
  • To elucidate the metabolic functions and roles of identified thermogenic compounds.
  • To identify novel genes involved in uncoupling protein 1 (Ucp1)-dependent thermogenesis.

Main Methods:

  • High-throughput screening of 4800 diverse compounds using a cell-based platform to induce Ucp1 expression in adipocytes.
  • Characterization of a lead compound for its thermogenic effects and cytotoxicity.
  • In vivo studies using a diet-induced obesity mouse model.
  • Mechanistic studies involving mitochondrial biogenesis, respiration, and signaling pathways (PKA-MAPK).

Main Results:

  • A novel compound was identified that activates Ucp1, promoting adipocyte thermogenesis with minimal cytotoxicity.
  • Mice treated with the compound showed reduced weight gain, enhanced insulin sensitivity, and increased energy expenditure.
  • The compound increased mitochondrial biogenesis and maximal respiration, partly via the PKA-MAPK pathway.
  • Two novel Ucp1-dependent thermogenic genes, Kcnc2 and Gm5627, were identified.

Conclusions:

  • The identified compound shows potential as a therapeutic agent for obesity and associated metabolic disorders.
  • The newly identified genes, Kcnc2 and Gm5627, play significant roles in Ucp1-dependent thermogenesis.

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