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. 2025 Mar;168(3):508-524.
doi: 10.1053/j.gastro.2024.10.034. Epub 2024 Nov 8.

Creeping Fat-Derived Free Fatty Acids Induce Hyperplasia of Intestinal Muscularis Propria Muscle Cells: A Novel Link Between Fat and Intestinal Stricture Formation in Crohn's Disease

Weiwei Liu  1 , Ren Mao  2 , Thi Hong Nga Le  1 , Gail West  1 , Venkateshwari Varadharajan  3 , Rakhee Banerjee  3 , Genevieve Doyon  1 , Pranab Mukherjee  1 , Quang Tam Nguyen  1 , Anny Mulya  1 , Julie H Rennison  3 , Ilyssa O Gordon  4 , Michael Cruise  4 , Shaomin Hu  4 , Doug Czarnecki  1 , Thomas Plesec  4 , Jyotsna Chandra  1 , Suhanti Banerjee  1 , Jie Wang  5 , William J Massey  1 , Idan Goren  1 , Si-Nan Lin  1 , Satya Kurada  6 , Benjamin L Cohen  7 , Taha Qazi  7 , Stefan D Holubar  8 , Jeremy Lipman  8 , Arielle Kanters  8 , Christy M Gliniak  9 , Philipp E Scherer  9 , Min-Hu Chen  10 , Britta Siegmund  11 , Andrei I Ivanov  1 , Claudio Fiocchi  12 , David R Van Wagoner  3 , J Mark Brown  3 , Florian Rieder  13
Affiliations

Creeping Fat-Derived Free Fatty Acids Induce Hyperplasia of Intestinal Muscularis Propria Muscle Cells: A Novel Link Between Fat and Intestinal Stricture Formation in Crohn's Disease

Weiwei Liu et al. Gastroenterology. 2025 Mar.

Abstract

Background & aims: In Crohn's disease, wrapping of mesenteric fat around the bowel wall, so-called "creeping fat," is highly associated with strictures. The strongest contributor to luminal narrowing in strictures is a thickening of the human intestinal muscularis propria (MP). We investigated creeping fat-derived factors and their effect on mechanisms of human intestinal MP smooth muscle cell (HIMC) hyperplasia.

Methods: Free fatty acids (FFAs) in creeping fat or noncreeping mesenteric fat organ cultures were measured via lipidomic mass spectrometry. Primary HIMCs were exposed to FFAs and cell proliferation was assessed. Intracellular FFA metabolism pathways and reactive oxygen species were functionally evaluated. Muscle thickness was investigated in dextran sodium sulfate colitis with small molecule inhibition of FFA transport and a novel fat deletion mouse model.

Results: Subserosal creeping fat is associated with a markedly thickened MP. Experimental deletion of mesenteric fat (FAT-ATTAC [fat apoptosis through targeted activation of caspase 8] mouse) reduced MP thickness. Human creeping fat-conditioned medium strongly up-regulated HIMC proliferation. Creeping fat released higher amounts of 5 long-chain FFAs, including palmitate. Inhibition of HIMC long-chain FFA metabolism or FFA uptake into mitochondria through carnitine palmitoyltransferase-1 reduced the palmitate-induced HIMC proliferation. Blockade of conversion of palmitate into phospholipids reduced HIMC proliferation. Prophylactic inhibition of carnitine palmitoyltransferase-1 in experimental dextran sodium sulfate colitis did not ameliorate inflammation, but reduced MP thickness.

Conclusions: Creeping fat-released long-chain FFAs induce a selective proliferative response by HIMC. These results point to creeping fat as a novel contributor to stricture formation in Crohn's disease.

Keywords: Anti-Fibrotic Therapy; Fibrostenosis; Hyperplasia; Hypertrophy; Lipidomics.

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Conflict of interest statement

I.O.G. receives research support from Celgene Corporation, Morphic Therapeutics, Alimentiv.

For all: IOG receives no direct funds; Cleveland Clinic receives funds on her behalf.

M.C. is consultant to Janssen, Takeda, Abbvie, China Medical System, Ipsen.

S.K. is consultant to Bristol Myers Squibb (BMS).

B.L.C receives the following financial support: Advisory Boards and Consultant for Abbvie, Celgene-Bristol Myers Squibb, Emmes Biopharma Services LLC (DSMB), Lilly, Pfizer, Sublimity Therapeutics, Takeda, TARGET RWE; CME Companies: Cornerstones, Vindico; Speaking: Abbvie; Educational Grant: Pfizer.

T.Q. is a consultant for Abbvie, Celgene/Bristol Meyers Squibb (BMS), Prometheus Biosciences, and Janssen.

S.D.H is a consultant to Takeda.

B.S. is a consultant for AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Endpoint Health, Falk Pharma, Galapagos, Gilead, Janssen, Landos, Pfizer, Prometheus, and Takeda; has received speaker fees from AbbVie, CED Service GmbH, Eli Lilly, Falk Pharma, Ferring, Galapagos, Janssen, Novartis, Pfizer, and Takeda.

C.F. received speaker fees from UCB, Genentech, Sandoz, Janssen and he is consultant for Athos Therapeutics, Inc.

F.R. is consultant to Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, Astra Zeneca, Bausch & Lomb, Boehringer-Ingelheim, Celgene/BMS, Celltrion, CDISC, Celsius, Cowen, Eugit, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Jannsen, Koutif, Mestag, Metacrine, Mirum, Mopac, Morphic, Myka Labs, Organovo, Origo, Palisade, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, Trix Bio, UCB, Ysios, 89Bio

All other authors declared no conflict of interest.

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