bims-ciryme 2025-08-17 papers

Nat Immunol. 2025 Aug 13.

Circadian circuits control plasticity of group 3 innate lymphoid cells by sustaining epigenetic configuration of RORγt.

Bishan Bhattarai, Alina Ulezko Antonova, Jose L Fachi, Leone S Hopkins, Matthew V D McCullen, Ankita Saini, Sarah de Oliveira, Wandy L Beatty, Erik S Musiek, Vijay K Kuchroo, Mitchell A Lazar, Eugene M Oltz, Marco Colonna.

The gut experiences daily fluctuations in microbes and nutrients aligned with circadian rhythms that regulate nutrient absorption and immune function. Group 3 innate lymphoid cells (ILC3s) support gut homeostasis through interleukin-22 (IL-22) but can convert into interferon-γ-producing ILC1s. How circadian proteins control this plasticity remains unclear. Here we showed that the circadian proteins REV-ERBα and REV-ERBβ maintain ILC3 identity. Their combined deletion promoted ILC3-to-ILC1 conversion, reduced energy metabolism and IL-22 production, increased interferon-γ production, and heightened susceptibility to Citrobacter rodentium infection. Single-cell multiomics and gene editing revealed that REV-ERBα/REV-ERBβ deficiency upregulated the transcription factor NFIL3, which repressed the expression of RORγt via a -2-kb cis-regulatory element in the Rorc gene, shifting cells toward a T-bet-driven state. Chromatin and metabolic analyses indicated that REV-ERBα/REV-ERBβ loss reprogrammed regulatory and metabolic circuits. Thus, REV-ERBα/REV-ERBβ safeguard gut integrity by regulating clock genes that control RORγt expression and preserve ILC3 identity and resistance to intestinal inflammation.

DOI: https://doi.org/10.1038/s41590-025-02240-5

Cell Rep. 2025 Aug 12. pii: S2211-1247(25)00912-X. [Epub ahead of print]44(8): 116141

Circadian clocks and periodic anticipated fasting prevent fasting-associated hepatic steatosis in calorie restriction.

Oghogho P Ebeigbe, Volha Mezhnina, Artem Astafev, Nikkhil Velingkaar, Jillian Kodger, Allan Poe, Jonathan Fritz, Kadaia Z Williams, Evelina Trokhimenko, Josefa-Marie B Rom, Yana Sandlers, Roman V Kondratov.

Calorie restriction (CR) improves health and longevity. CR induces a periodic fasting cycle in mammals; our study compares CR with unanticipated fasting (F), when the food is unexpectedly withheld. F induces hepatic steatosis, whereas CR reduces it; surprisingly, the difference is not due to hepatic β-oxidation. Liver transcriptome analysis identifies fatty acid transporters (Slc27a1 and Slc27a2), triglyceride (TAG) synthesis (Gpat4), and lipid storage (Plin2 and Cidec) genes to be upregulated only in F, in agreement with hepatic steatosis. The circadian clock and anticipated fasting contribute to preventing fasting-associated hepatic steatosis in CR. Mechanistically, the Slc27a1, Plin2, and Cidec genes are upregulated, and liver TAGs accumulate in circadian clock mutant mice on CR or if wild-type CR mice miss their anticipated meal. The results highlight the similarities and differences between F and CR, suggesting that circadian clock-dependent gating of transcriptional response to fasting controls lipid homeostasis and prevents hepatic steatosis.

Keywords: CP: Metabolism; Calorie restriction; circadian clock; circadian rhythms; dietary intervention; fasting; fatty acid metabolism; lipid metabolism; steatosis; triglyceride

DOI: https://doi.org/10.1016/j.celrep.2025.116141

FASEB J. 2025 Aug 15. 39(15): e70918

Pharmacological but Not Physiological Levels of GDF15 and FGF21 Regulate Body Weight and Glycemic Control in Obese Mice.

Sarah Engelbeen, Julie Mie Jacobsen, Luisa Deisen, Elisa Parsche, Alberte Buch-Ramussen, Christoffer Clemmensen, Rune Ehrenreich Kuhre, Kornelia Johann, Maximilian Kleinert.

GDF15 and FGF21 are stress-induced hormone-like factors with putative roles in the regulation of energy homeostasis. Since their plasma levels increase with obesity, it has been proposed that GDF15 and FGF21 jointly impose a cap on weight gain during diet-induced obesity. To test this hypothesis, we generated single Gdf15 knockout (KO) and Fgf21 KO, and double Gdf15/Fgf21 KO mice. Depletion of both GDF15 and FGF21 had minimal effects on the gain of body weight, fat, and fat-free mass in male or female mice fed either chow diet or high-fat, high-sucrose diet. Similarly, glucose tolerance, fasting glucose, and plasma insulin levels were largely unaffected by the combined absence of GDF15 and FGF21. Thus, combined deletion of endogenous Gdf15 and Fgf21 exerted a limited influence on body weight gain or glycaemic control. By contrast, pharmacological dosing of obese male mice with long-acting recombinant GDF15 or FGF21 produced meaningful weight loss on their own (8%-10%), and GDF15 + FGF21 co-administration yielded an impressive, additive weight reduction of 25%. Combinatorial treatment also improved glucose tolerance, lowered fasting insulin levels, and reduced hepatic fat content. In conclusion, while endogenous GDF15 and FGF21 appear largely nonessential for the regulation of weight gain and glycemia, pharmacological co-treatment with GDF15 and FGF21 elicits robust weight-loss benefits.

Keywords: FGF21; GDF15; diet‐induced obesity; energy homeostasis regulation; gene knockout mice; glucose tolerance; pharmacological weight‐loss therapy

DOI: https://doi.org/10.1096/fj.202501350R