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The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans.

ABSTRACT: The insulin-sensitizer pioglitazone exerts its cardiometabolic benefits in type 2 diabetes (T2D) through a redistribution of body fat, from ectopic and visceral areas to subcutaneous adipose depots. Whereas excessive weight gain and lipid storage in obesity promotes insulin resistance and chronic inflammation, the expansion of subcutaneous adipose by pioglitazone is associated with a reversal of these immunometabolic deficits. The precise events driving this beneficial remodeling of adipose tissue with pioglitazone remain unclear, and whether insulin-sensitizers alter the lipidomic composition of human adipose has not previously been investigated. Using shotgun lipidomics, we explored the molecular lipid responses in subcutaneous adipose tissue following 6months of pioglitazone treatment (45mg/day) in obese humans with T2D. Despite an expected increase in body weight following pioglitazone treatment, no robust effects were observed on the composition of storage lipids (i.e., triglycerides) or the content of lipotoxic lipid species (e.g., ceramides and diacylglycerides) in adipose tissue. Instead, pioglitazone caused a selective remodeling of the glycerophospholipid pool, characterized by a decrease in lipids enriched for arachidonic acid, such as plasmanylethanolamines and phosphatidylinositols. This contributed to a greater overall saturation and shortened chain length of fatty acyl groups within cell membrane lipids, changes that are consistent with the purported induction of adipogenesis by pioglitazone. The mechanism through which pioglitazone lowered adipose tissue arachidonic acid, a major modulator of inflammatory pathways, did not involve alterations in phospholipase gene expression but was associated with a reduction in its precursor linoleic acid, an effect that was also observed in skeletal muscle samples from the same subjects. These findings offer important insights into the biological mechanisms through which pioglitazone protects the immunometabolic health of adipocytes in the face of increased lipid storage.

SUBMITTER: Palavicini JP

PROVIDER: S-EPMC8674727 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The biological mechanisms linking obesity to insulin resistance have not been fully elucidated. We have shown that insulin resistance or glucose intolerance in diet-induced obese mice is related to a shift in the ratio of pro- and anti-inflammatory T cells in adipose tissue. We sought to test the hypothesis that the balance of T-cell phenotypes would be similarly related to insulin resistance in human obesity.Healthy overweight or obese human subjects underwent adipose-tissue biopsies and quantification of insulin-mediated glucose disposal by the modified insulin suppression test. T-cell subsets were quantified by flow cytometry in visceral (VAT) and subcutaneous adipose tissue (SAT). Results showed that CD4 and CD8 T cells infiltrate both depots, with proinflammatory T-helper (Th)-1, Th17, and CD8 T cells, significantly more frequent in VAT as compared with SAT. T-cell profiles in SAT and VAT correlated significantly with one another and with peripheral blood. Th1 frequency in SAT and VAT correlated directly, whereas Th2 frequency in VAT correlated inversely, with plasma high-sensitivity C-reactive protein concentrations. Th2 in both depots and peripheral blood was inversely associated with systemic insulin resistance. Furthermore, Th1 in SAT correlated with plasma interleukin-6. Relative expression of associated cytokines, measured by real-time polymerase chain reaction, reflected flow cytometry results. Most notably, adipose tissue expression of anti-inflammatory interleukin-10 was inversely associated with insulin resistance.CD4 and CD8 T cells populate human adipose tissue and the relative frequency of Th1 and Th2 are highly associated with systemic inflammation and insulin resistance. These findings point to the adaptive immune system as a potential mediator between obesity and insulin resistance or inflammation. Identification of antigenic stimuli in adipose tissue may yield novel targets for treatment of obesity-associated metabolic disease.

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The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans.

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