The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans
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 in...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:335d5896954c4b0ea9323a843dc2c1dd2021-12-02T09:53:20ZThe Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans1664-042X10.3389/fphys.2021.784391https://doaj.org/article/335d5896954c4b0ea9323a843dc2c1dd2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphys.2021.784391/fullhttps://doaj.org/toc/1664-042XThe 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.Juan P. PalaviciniJuan P. PalaviciniAlberto Chavez-VelazquezMarcel FourcaudotDevjit TripathyMeixia PanMeixia PanLuke NortonRalph A. DeFronzoChristopher E. ShannonFrontiers Media S.A.articleadiposeobesitylipidomicspioglitazonetype 2 diabetesPhysiologyQP1-981ENFrontiers in Physiology, Vol 12 (2021) |
| institution |
DOAJ |
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DOAJ |
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| topic |
adipose obesity lipidomics pioglitazone type 2 diabetes Physiology QP1-981 |
| spellingShingle |
adipose obesity lipidomics pioglitazone type 2 diabetes Physiology QP1-981 Juan P. Palavicini Juan P. Palavicini Alberto Chavez-Velazquez Marcel Fourcaudot Devjit Tripathy Meixia Pan Meixia Pan Luke Norton Ralph A. DeFronzo Christopher E. Shannon The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans |
| description |
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. |
| format |
article |
| author |
Juan P. Palavicini Juan P. Palavicini Alberto Chavez-Velazquez Marcel Fourcaudot Devjit Tripathy Meixia Pan Meixia Pan Luke Norton Ralph A. DeFronzo Christopher E. Shannon |
| author_facet |
Juan P. Palavicini Juan P. Palavicini Alberto Chavez-Velazquez Marcel Fourcaudot Devjit Tripathy Meixia Pan Meixia Pan Luke Norton Ralph A. DeFronzo Christopher E. Shannon |
| author_sort |
Juan P. Palavicini |
| title |
The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans |
| title_short |
The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans |
| title_full |
The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans |
| title_fullStr |
The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans |
| title_full_unstemmed |
The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans |
| title_sort |
insulin-sensitizer pioglitazone remodels adipose tissue phospholipids in humans |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/335d5896954c4b0ea9323a843dc2c1dd |
| work_keys_str_mv |
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