Fatty Acid Composition, at Equivalent Lipid Exposure, Dictates Human Macrophage Polarization via PPARγ Signaling

AlSaeed, Halemah; Almusallam, Hesah; Menezes, Shayndel; Almelaifi, Hessah; Alonaizi, Hussah; Almejaimi, Mohammad; Ahmad, Rasheed; Al-Rashed, Fatema

doi:10.3390/cells15030308

Open AccessArticle

Fatty Acid Composition, at Equivalent Lipid Exposure, Dictates Human Macrophage Polarization via PPARγ Signaling

by

Halemah AlSaeed

^1,†

,

Hesah Almusallam

^2,†,

Shayndel Menezes

¹,

Hessah Almelaifi

¹,

Hussah Alonaizi

¹

,

Mohammad Almejaimi

¹

,

Rasheed Ahmad

^1,*

and

Fatema Al-Rashed

^1,*

¹

Immunology and Microbiology Department, Dasman Diabetes Institute, Al-Soor Street, P.O. Box 1180, Dasman, Kuwait City 15462, Kuwait

²

Animal and Imaging Core Facility, Dasman Diabetes Institute, Dasman, Kuwait City 15462, Kuwait

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Cells 2026, 15(3), 308; https://doi.org/10.3390/cells15030308

Submission received: 14 January 2026 / Revised: 1 February 2026 / Accepted: 3 February 2026 / Published: 6 February 2026

(This article belongs to the Collection Research Advances in Cellular Metabolism)

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Abstract

Dietary fats are consumed as mixtures, yet it remains unclear whether fatty acid composition, independent of fat content, dictates human macrophage polarization. We compared two defined mixtures containing identical fatty acids (palmitic, oleic, and linoleic acids) in different ratios: a palmitate-enriched mixture (4:3:3) and an unsaturated fat-dominant mixture (2:4:4). In primary human monocyte-derived macrophages, palmitate enrichment increased CD14+CD11b+HLA-DR+ pro-inflammatory polarization, whereas the unsaturated fat-dominant mixture increased CD14+CD11b+CD163+ anti-inflammatory polarization. Mechanistic studies in THP-1-derived macrophages recapitulated these phenotype shifts and identified a reciprocal nuclear-receptor program: palmitate enrichment induced peroxisome proliferator-activated receptor gamma (PPARγ), together with ER-stress mediators EIF2AK3 and DDIT3, while the unsaturated fat-dominant mixture preferentially induced PPARα and IRF4. Pharmacologic modulation demonstrated functional dependence on PPARγ: GW9662 attenuated palmitate-driven M1-like polarization, whereas rosiglitazone disrupted the protective program under unsaturated fat-dominant conditions. These findings show that fatty acid composition, at equivalent total lipid concentration, is a dominant determinant of human macrophage inflammatory fate and highlight PPARγ as a context-dependent lipid sensor.

Keywords: PPARs; fatty acid; high fat diet; inflammation; macrophages

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MDPI and ACS Style

AlSaeed, H.; Almusallam, H.; Menezes, S.; Almelaifi, H.; Alonaizi, H.; Almejaimi, M.; Ahmad, R.; Al-Rashed, F. Fatty Acid Composition, at Equivalent Lipid Exposure, Dictates Human Macrophage Polarization via PPARγ Signaling. Cells 2026, 15, 308. https://doi.org/10.3390/cells15030308

AMA Style

AlSaeed H, Almusallam H, Menezes S, Almelaifi H, Alonaizi H, Almejaimi M, Ahmad R, Al-Rashed F. Fatty Acid Composition, at Equivalent Lipid Exposure, Dictates Human Macrophage Polarization via PPARγ Signaling. Cells. 2026; 15(3):308. https://doi.org/10.3390/cells15030308

Chicago/Turabian Style

AlSaeed, Halemah, Hesah Almusallam, Shayndel Menezes, Hessah Almelaifi, Hussah Alonaizi, Mohammad Almejaimi, Rasheed Ahmad, and Fatema Al-Rashed. 2026. "Fatty Acid Composition, at Equivalent Lipid Exposure, Dictates Human Macrophage Polarization via PPARγ Signaling" Cells 15, no. 3: 308. https://doi.org/10.3390/cells15030308

APA Style

AlSaeed, H., Almusallam, H., Menezes, S., Almelaifi, H., Alonaizi, H., Almejaimi, M., Ahmad, R., & Al-Rashed, F. (2026). Fatty Acid Composition, at Equivalent Lipid Exposure, Dictates Human Macrophage Polarization via PPARγ Signaling. Cells, 15(3), 308. https://doi.org/10.3390/cells15030308

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Fatty Acid Composition, at Equivalent Lipid Exposure, Dictates Human Macrophage Polarization via PPARγ Signaling

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