Pioglitazone Treatment Reduces Adipose Tissue Inflammation through Reduction of Mast Cell and Macrophage Number and by Improving Vascularity

Abstract

Context and ObjectiveAdipose tissue in insulin resistant subjects contains inflammatory cells and extracellular matrix components. This study examined adipose pathology of insulin resistant subjects who were treated with pioglitazone or fish oil.Design, Setting and ParticipantsAdipose biopsies were examined from nine insulin resistant subjects before/after treatment with pioglitazone 45 mg/day for 12 weeks and also from 19 subjects who were treated with fish oil (1,860 mg EPA, 1,500 mg DHA daily). These studies were performed in a clinical research center setting.ResultsPioglitazone treatment increased the cross-sectional area of adipocytes by 18% (p = 0.01), and also increased capillary density without affecting larger vessels. Pioglitazone treatment decreased total adipose macrophage number by 26%, with a 56% decrease in M1 macrophages and an increase in M2 macrophages. Mast cells were more abundant in obese versus lean subjects, and were decreased from 24 to 13 cells/mm2 (p = 0.02) in patients treated with pioglitazone, but not in subjects treated with FO. Although there were no changes in total collagen protein, pioglitazone increased the amount of elastin protein in adipose by 6-fold.ConclusionThe PPARγ agonist pioglitazone increased adipocyte size yet improved other features of adipose, increasing capillary number and reducing mast cells and inflammatory macrophages. The increase in elastin may better permit adipocyte expansion without triggering cell necrosis and an inflammatory reaction.

Do adipose tissue macrophages promote insulin resistance or adipose tissue remodelling in humans?

“…Treatment with thiazolidinediones, a agonist of PPARγ, reduced macrophage number in adipose tissue, in parallel with improved insulin sensitivity by triggering apoptosis of M1 macrophages and increasing M2 macrophages [70,71]. Administration of a recombinant adenovirus Glucagon-like peptide-1 (GLP-1) to diabetic ob/ob mice reduced fat mass, adipocyte size, M1 macrophages, and production of inflammatory cytokines [72].…”

Insulin-resistant subjects have normal angiogenic response to aerobic exercise training in skeletal muscle, but not in adipose tissue

“…; Spencer et al. ). However, it remains unknown whether exercise training affects adipose tissue vascularity in humans.…”

“…Accordingly, decreased vessel density has been observed in subcutaneous fat from obese versus lean humans (Pasarica et al 2009;Spencer et al 2011), and postprandial adipose tissue blood flow is positively correlated with adipose tissue insulin sensitivity (Karpe et al 2002). Furthermore, the TZDs pioglitazone and rosiglitazone induce adipose tissue angiogenesis (Gealekman et al 2012;Spencer et al 2014). However, it remains unknown whether exercise training affects adipose tissue vascularity in humans.…”

For Value or for Worth? Part 2: A Neuroeconomical Thought-Action-Mood-Space Modulated by (Un-)Certainty as Sign- or Goal-tracking

“…Therefore pioneers in ST-research [126] and MC-research related to the brain [58], Rae Silver, now leader in circadian rhythms, not fully by chance are immediate neighbors in a monograph on motivation [185], and the links likely also run via "clocked" [186] and "clocking" [187] MCs in brain [58] and other tissue [188] in relation to bio-economic metabolism [189] and its central "subjective" variable effort [190].…”