Telmisartan induces browning of fully differentiated white adipocytes via M2 macrophage polarization

Sci Rep. 2019 Feb 4;9(1):1236. doi: 10.1038/s41598-018-38399-1.

Abstract

Telmisartan is a well-known anti-hypertensive drug acting as an angiotensin 2 receptor blocker (ARB), but it also possesses partial PPARγ agonistic activity and induces insulin sensitivity. In the present study, we investigated the effects of telmisartan on macrophage polarization in association with its browning capacity, because PPARγ plays a key role in M2 polarization and in the browning of white adipocytes. Telmisartan induced M2 marker expression in murine macrophages concentration dependently, which was confirmed by flow cytometry. Both PPARγ and PPARδ activations appear to be responsible for telmisartan-induced M2 polarization. Telmisartan-treated conditioned medium (Tel-CM) of RAW264.7 cells and of bone marrow derived macrophages (BMDM) induced the expressions of browning markers in fully differentiated white adipocytes with reduced lipid droplets, and increased oxygen consumption rate and mitochondrial biogenesis. Levels of catecholamines (CA) released into the conditioned medium as well as intracellular tyrosine hydroxylase (TH) mRNAs were found to be increased by telmisartan, and browning effects of Tel-CM were lessened by β3 receptor antagonist (L-748,337), suggesting CA secreted into CM play a role in Tel-CM-induced adipocyte browning. Acute administration of telmisartan (2 weeks, p.o.) to C57BL/6J mice increased the expressions of browning markers and M2 markers in white adipose tissues, whereas macrophage depletion by clodronate liposome pretreatment attenuated the telmisartan-induced expressions of browning markers. Together, telmisartan was observed to induce the browning of fully differentiated white adipocytes, at least in part, via PPAR activation-mediated M2 polarization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Brown / drug effects*
  • Adipocytes, Brown / metabolism
  • Adipocytes, White / drug effects*
  • Adipocytes, White / metabolism
  • Adipose Tissue, White / cytology
  • Adipose Tissue, White / drug effects
  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Animals
  • Catecholamines / metabolism
  • Cell Differentiation
  • Clodronic Acid / pharmacology
  • Culture Media, Conditioned / metabolism
  • Humans
  • Insulin Resistance
  • Macrophage Activation / drug effects*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Obesity / drug therapy
  • PPAR gamma / agonists
  • PPAR gamma / metabolism
  • RAW 264.7 Cells
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Telmisartan / pharmacology*
  • Telmisartan / therapeutic use

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Catecholamines
  • Culture Media, Conditioned
  • PPAR gamma
  • Ppard protein, mouse
  • Pparg protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Clodronic Acid
  • Telmisartan