President's Oral Session: Abstracts of Distinction

(OR14-04-25) Role of Myeloid Acyl CoA Synthetase 4 in Diet-Induced Obesity

Monday, June 2, 2025

10:36 AM – 10:48 AM ET

Location: S230 CD

Presenting Author(s)

Robin Wilson, PhD

Research Associate
Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University
Boston, Massachusetts, United States

Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.

Co-Author(s)

XS

Xiaotian Shen

Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University, United States
RF

Rong Fan

Cornell University
Ithaca, New York, United States
AA

Alaa M. Alfudhail

Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University, United States
SF

Sophia Fernandez

Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University, United States
BP

Brian Park

Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University, United States
BW

Blenda Wong

Brigham and Women's Hospital
Boston, Massachusetts, United States
MS

Matthew Spite

Brigham and Women's Hospital, United States
AG

Andrew S. Greenberg, M.D.

Professor
Tufts University
Boston, Massachusetts, United States

Objectives: To determine the role of acyl-CoA 4 (ACSL4) expression in myeloid cells in regulating diet-induced obesity

Methods: To investigate the role of ACSL4 in DIO, we generated mice with myeloid cell-specific deficiency of ACSL4 (ACSL4KO) by transferring the LysM cre transgene into ACSL4FL (floxed) mice. Male ACSL4FL and ACSL4KO mice were fed a 60% high fat diet (HFD). Body weight (every 2 weeks) and body composition (at 6 weeks and 12 weeks), energy expenditure (EE) using metabolic cages (at 6 weeks), and body surface temperature in interscapular and inguinal areas (at 7 weeks) were measured. After 12 weeks of HFD, an insulin tolerance test was performed. Mice were euthanized after 6 hours of fasting. Liver triglycerides were determined. Gonadal white adipose tissue (gWAT), and inguinal WAT (iWAT) were analyzed for adipocyte morphology. Brown adipose tissue (BAT) and iWAT were analyzed for expression of thermogenic and inflammatory markers by RT-PCR and western blotting.

Results: On HFD, in comparison to ACSL4FL mice, ACSL4KO gained significantly less body weight (p < 0.05) and fat mass (23 % reduction, p< 0.05); demonstrated increased EE (p < 0.01); and increased surface temperature in inguinal area (p < 0.01) but not in surface temperature of interscapular area. ACSL4KO mice had improved insulin tolerance (p < 0.01), and liver triglycerides (p < 0.05). ACSL4KO had reduced adipose depot weights (p < 0.05); and adipocyte size in iWAT and gWAT depot (p < 0.05). Gene expression of inflammatory markers were reduced; including F4/80 (macrophages), Cd11c (dendritic cells), and Ly6g (neutrophils) (p < 0.05) in iWAT. Western blot studies demonstrated increased phosphorylation of AMP activated protein kinase (AMPK). Gene expression of Pgc-1α was increased but no differences in expression of UCP1, Serca2b nor CKB .

Conclusions: ACSL4 deficiency in myeloid cells protects mice from DIO by increasing thermogenesis in iWAT independent of UCP1, Serca2b, and CKB expression. ACSL4 deficiency increases iWAT PGC-1α expression and AMPK activation indicating a novel pathway for beige thermogenesis. ACSL4 deficiency reduces iWAT inflammation and improved insulin sensitivity. Present studies are underway to further elucidate the mechanistic details of myeloid cell ACSL4 deficiency on DIO.

Funding Sources: ASG: USDA NIFA , USDA ARS , NIDDK P30DK2022-6708-37186.