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In PDE3B KO Mice, White Epididymal Adipose Tissue (WAT) Exhibits Phenotypic Characteristics of "Fat-burning" Brown Adipose Tissue (BAT), with reduced expression of pro-inflammatory markers, including the NLRP3 Inflammasome.

Monday, September 22, 2014 — Poster Session II

4:00 p.m. – 6:00 p.m.

FAES Academic Center

NHLBI

MOLBIO-6

Authors

  • FA Khan
  • YW Chung
  • Y Tang
  • SC Hockman
  • K Berger
  • EM Billings
  • O Gavrilova
  • E Guirguis
  • S Liu
  • Y Khan
  • K Huo
  • DM Schimel
  • AM Aponte
  • E Degerman
  • VC Manganiello

Abstract

In PDE3B KO mice WAT, cAMP/PKA- and AMPK-signaling pathways are activated, assuming BAT phenotypic characteristics, including increased genes expression, such as PGC-1α, PDRM16, LRP130, and Elovl3, important in mitochondrial biogenesis, induction of thermogenic program. In KO WAT, there is coordinate regulation of expression of genes, transcriptional regulators, mitochondrial proteins required for energy dissipation and fatty acid oxidation, such as PPARα, ATGL, perilipin, UCP-1, CIDEA, and several mitochondrial proteins involved in electron transport and fatty acid β-oxidation. UCP-1, BAT “marker”, markedly elevated in KO WAT and contribute to smaller increase in body weight in response to high fat diets, uncoupled WAT mitochondrial respiration, increased oxygen consumption, increased fatty acid oxidation and treadmill endurance. In addition, expression of inflammation-related genes was decreased in KO WAT, including some whose reduced expression reflect reduced monocyte/ macrophage infiltration/differentiation in KO EWAT as well as reduction in NLRP3 inflammasome. These results suggest that PDE3B may regulate a cAMP-sensitive “switch” for WAT/BAT phenotypic conversion, regulating downstream effects of cAMP on cAMP/PKA- and AMPK-signaling, mitochondrial biogenesis and function, energy dissipation, and pro-inflammatory state of WAT. Understanding mechanisms for WAT to BAT conversion in KO WAT, with reduced inflammation, represents a potential strategy in treatment of obesity and diabetes.

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