Deleting TGF-β1 from CD206+ M2 macrophages preserved muscle in mice fed a high-fat diet for twelve weeks — without making them any lighter than the controls.
Obesity does something to muscle that is not simply a matter of carrying more weight. Muscle mass and function decline, fibrous tissue accumulates, and the combination of excess fat with diminished muscle is a worse clinical picture than either alone — particularly in older people, where it compounds into frailty.
A study in the Journal of Cachexia, Sarcopenia and Muscle from the University of Toyama locates one driver of that decline in an unexpected place: not in the muscle, and not in the fat, but in a population of immune cells, and in one signalling molecule they secrete.
The research team was led by Kazuyuki Tobe, a distinguished research professor at Toyama’s Research Center for Pre-Disease Science, with Muhammad Bilal and Shiho Fujisaka of the School of Medicine among the team.
One molecule, one cell type
The experiment used mice engineered so that TGF-β1 could be deleted specifically in CD206+ M2 macrophages, then fed a high-fat diet for twelve weeks alongside controls.
The specificity is what makes the result interpretable. TGF-β1 is one of the most widely used signalling molecules in the body — involved in wound healing, immune regulation, fibrosis and development — so deleting it everywhere would produce effects impossible to attribute to anything. Removing it from one macrophage subtype asks a narrow question: what does this particular cell population’s TGF-β1 do?
M2 macrophages are the alternatively activated kind, usually described as the repair-associated counterpart to inflammatory M1 cells. That framing is a simplification of a spectrum, and this result complicates it usefully, since the repair-associated population turns out to be doing something harmful in this context.
The knockout mice reached body weights similar to the controls, which is the single most important number in the study. They got just as fat. Everything that follows is therefore not a consequence of being leaner.
What changed
The functional differences were large. Knockout mice ran roughly twice as far before exhaustion, had greater grip strength and hung longer in a suspension test. They also showed improved glucose tolerance and insulin sensitivity.
The tissue matched the performance: more skeletal muscle mass, larger muscle fibres, increased lean mass, and reduced expression of fibrosis-related genes.
Two mechanisms were identified, and they run through different tissues.
The first is local. Losing TGF-β1 activated fibro-adipogenic progenitors — resident muscle cells that, depending on the signals they receive, either support repair or turn into fat and scar tissue. Activated, they increased production of follistatin and follistatin-like protein 1, both linked to the formation of new muscle fibres. Since TGF-β1 is the canonical pro-fibrotic signal, removing it from the macrophages sitting among these progenitors plausibly flips their output from scar to muscle.
The second is systemic and more surprising. Fat tissue in the knockout mice secreted more adiponectin, a hormone from fat that improves insulin sensitivity and is characteristically suppressed in obesity. Adiponectin acted on AdipoR1 receptors in muscle and switched on the AMPK/SIRT1/PGC-1α pathway.
“The activation of this pathway resulted in enhanced mitochondrial function and fatty acid oxidation,” Tobe said.
That pathway is a well-mapped endurance programme — PGC-1α drives mitochondrial biogenesis, and it is among the things exercise and metformin converge on. A doubling of running distance is what you would expect from switching it on.
The careful reading
The authors note that the study was conducted in mice and that further work is needed before any human application. Several features of the design deserve emphasis beyond that.
This was a genetic deletion present throughout the high-fat feeding period, not a treatment given to an animal that already had the problem. It establishes that TGF-β1 from these macrophages is necessary for obesity-induced muscle dysfunction to develop, which is a different and weaker claim than showing that blocking it later would reverse anything.
There is also no drug. Targeting TGF-β1 pharmacologically has been attempted for decades in fibrosis and oncology, and the difficulty is precisely its ubiquity: systemic inhibition carries cardiac and immune toxicity, and delivering an inhibitor to one macrophage subtype in one tissue is not currently achievable. The cell-type-specific deletion that makes this experiment clean is also what makes it hard to translate.
The mice were young, and they were obese rather than old. Tobe’s extrapolation goes further than that: “If the TGF-β1 gene in M2 macrophages could be removed in humans, older people with sarcopenia might regain muscle mass,” he said, adding that such patients might become able to move more quickly and independently. Age-related sarcopenia and obesity-induced muscle dysfunction share features and are not the same condition, and nothing in this study was tested in an aged animal.
One point on the disclosures. The release states that the authors declare no conflicts of interest, and the funding list includes grant support from Boehringer Ingelheim, Novo Nordisk Pharma and an Eli Lilly Japan innovation research grant, alongside the Moonshot Research and Development Program, JSPS and a long list of Japanese medical foundations. Unrestricted research grants from pharmaceutical companies are routine in Japanese diabetes and metabolism research and do not amount to a conflict in themselves, but a reader is better served by seeing both statements together than by either alone.
The paper was published online on 18 June 2026.
Notes
- “Deletion of Tgf-β1 From CD206+ M2 Macrophages Ameliorates Obesity-Induced Suppression of Myogenesis and AMPK Phosphorylation in Skeletal Muscle.” Journal of Cachexia, Sarcopenia and Muscle, volume 17, issue 3, 2026. DOI: 10.1002/jcsm.70322.
- University of Toyama. “Immune cells may hold the key to fighting obesity-induced muscle dysfunction.” EurekAlert!, 4 August 2026. https://www.eurekalert.org/news-releases/1138631.
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