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. 2026 Apr 1;75(6):938–950. doi: 10.2337/db25-0466

Gut-Derived FGF15 Modulates Lean Mass, Bone, and Bile Acid Responses to Weight Loss

Nadejda Bozadjieva-Kramer 1,2, Garrett McMahon 2, Ziru Li 3,4, Jordan Wean 2, Jae Hoon Shin 2, Andriy Myronovych 2, Robert W O’Rourke 1,2, Ormond A MacDougald 3,5, Randy J Seeley 2,✉
PMCID: PMC13191413  PMID: 41920187

Abstract

Dietary, surgical, and pharmacological methods can effectively reduce body weight; however, rapid weight loss can also be accompanied by a loss of lean mass. Previously, we found that intestinal fibroblast growth factor 15 (FGF15; mouse ortholog of human FGF19) protects against lean mass loss after sleeve gastrectomy in mice and that circulating FGF19 predicts lean mass retention after very-low-energy diets in humans. We investigated the regulatory functions of intestine-derived FGF15 in lean and bone mass, glucose tolerance, and changes in bile acid and lipid parameters after weight loss in mice. Rapid weight loss was induced either by transitioning high-fat diet–fed intestine-specific FGF15–knockout and control mice to standard chow for 25 days or by administering daily semaglutide. Semaglutide decreased body weight, fat mass, and lean mass, all of which returned to baseline levels after treatment cessation. Lean mass was not preserved during dietary intervention in mice lacking FGF15, whereas semaglutide decreased lean mass irrespective of FGF15. Dietary intervention reduced hepatic triglyceride levels more efficiently, whereas greater improvement in glucose tolerance was observed with semaglutide. Semaglutide modulated shifts in bile acid composition, with particularly pronounced changes seen in the absence of FGF15. These data indicate that multiple factors, including intervention strategy and dietary context, modulate gut–liver and muscle communication and preservation of lean mass.

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Article Highlights

  • We evaluated the role of intestinal fibroblast growth factor 15 (FGF15) in regulating lean mass, glucose tolerance, bile acid, and lipid profiles after diet-induced compared with semaglutide-induced weight loss in mice.

  • Mice lacking FGF15 lost more lean mass during dietary intervention, whereas semaglutide decreased lean mass irrespective of FGF15; dietary intervention reduced hepatic triglyceride levels more efficiently, whereas greater improvement in glucose tolerance and elevated cecal bile acid levels were observed with semaglutide; and loss of FGF15 altered bile acid levels, whereas semaglutide treatment further regulated these levels in both genotypes, with particularly pronounced changes observed in the absence of FGF15.

  • Weight-loss intervention strategy and dietary context modulate gut–liver and muscle communication and preservation of lean mass.

Introduction

The global rise in obesity and its associated comorbidities, such as type 2 diabetes and metabolic dysfunction–associated fatty liver, poses a significant public health challenge (1,2). The Western lifestyle, characterized by high-calorie diets and sedentary habits, is a major contributor to this epidemic. High-fat diets (HFDs) alter enterohepatic circulation and modify bile acid composition, which profoundly affects the gut–liver axis and nutrient processing. Previous studies have shown that diet, surgery, and pharmacological approaches reduce body weight in humans and rodent models of obesity. However, rapid weight loss is often coupled with a loss of lean mass, a major concern in weight-loss interventions, including very-low-energy diets (VLEDs), pharmacological treatments, and metabolic surgery (3–6). Preserving lean mass during weight loss can help maintain energy expenditure by minimizing metabolic adaptation (7–9), thereby lowering the risk of weight regain (10). As a result, there is growing interest in elucidating the molecular mechanisms underlying lean mass loss during rapid weight reduction.

Fibroblast growth factor 15/19 (FGF15/19; mouse/human ortholog) is a gut hormone expressed in ileal enterocytes of the small intestine and is released postprandially in response to nutrient absorption (11–14). Once released from the ileum, FGF15/19 enters portal venous circulation and travels to the liver, where it binds to its receptor, FGFR4, and represses de novo bile acid synthesis (11). Individuals with obesity have reduced circulating FGF19 levels, suggesting a potential role of FGF15/19 in metabolic regulation (15–19). Importantly, plasma FGF19 levels increase in humans after bariatric surgery, such as vertical sleeve gastrectomy (VSG) (17,20–26). When evaluating the role of FGF15 in a VSG mouse model, we reported that mice lacking intestinal FGF15 showed greater lean mass loss after rapid weight loss induced by VSG (27). Subsequently, we examined whether nonsurgically induced rapid weight loss increased systemic FGF19 concentrations and whether FGF19 levels predicted lean mass loss after VLED-induced rapid weight loss in human participants with obesity. Our data showed that baseline (obesity) FGF19 levels, but not post-VLED FGF19 levels, significantly predicted the percentage of lean mass after VLED-induced weight loss (28). Together, these studies suggest that gut–muscle communication links intestinal FGF15/19 to the regulation of lean mass after VSG- and VLED-induced weight loss.

In this study, we investigated the effects of intestine-derived FGF15 on lean and bone mass, glucose tolerance, and bile acid and lipid profiles after two weight-loss strategies in mice. Rapid weight loss was implemented either by switching intestine-specific FGF15–knockout (FGF15INT-KO) and control mice to a standard chow diet for 25 days or through daily administration of semaglutide, a glucagon-like peptide 1 receptor agonist (GLP-1RA), while the mice remained on an HFD. Semaglutide treatment resulted in reductions in body weight, fat, and lean mass, with these parameters returning to baseline levels after discontinuation. Mice lacking FGF15 had a greater loss in lean mass during dietary intervention, whereas semaglutide reduced lean mass regardless of intestinal FGF15 status. Changes in bone and bone marrow adipose tissue (BMAT) parameters depended on diet, weight-loss intervention, and intestinal FGF15. Compared with semaglutide, dietary intervention was more effective in reducing hepatic triglyceride levels, whereas semaglutide produced greater improvements in glucose tolerance. Additionally, control mice receiving semaglutide demonstrated increased conversion to secondary bile acids and higher total cecal bile acid content. These results suggest that communication between the gut, liver, and muscle depends on several variables, including the type of weight-loss intervention and dietary conditions.

Research Design and Methods

Study Approval

All protocols complied with all relevant ethical regulations for animal and human subject research. All protocols were approved by the University of Michigan (Ann Arbor, MI) and were in accordance with National Institutes of Health guidelines.

Animals, Metabolic Studies, and Diets

Male mice were group housed with ad libitum access to food and water. They were kept under a 12-h light/dark cycle in a facility maintained at 25°C and 50% to 60% humidity. FGF15 flox/flox mice were generated using CRISPR-Cas9 technology, with LoxP sites flanking exon 2 of the FGF15 gene, as previously described (27). These mice were then bred with VilCreERT2 mice (C57BL/6J background). Tamoxifen (150 mg/kg; three doses with 48-h intervals) was administered intraperitoneally to both VilCreERT2;Fgf15 flox/flox and wild-type (WT) control (FGF15 flox/flox and VilCreERT2) mice. Excision of exon 2 was validated within the ileum, where FGF15 is most highly expressed.

After tamoxifen administration, male FGF15INT-KO and control WT mice (littermates) were initially fed a standard chow diet (cat. no. 5LOD; PicoLab) until 13 weeks of age, when they were transitioned to a 60% HFD (cat. no. 12492; Research Diets, Inc.). All mice were fed an HFD for 22 weeks. We used stratified randomization to assign mice to intervention groups. After 22 weeks of HFD feeding, half of the mice (control n = 8; FGF15INT-KO n = 8) were switched back to the regular chow diet (cat. no. 5LOD; PicoLab) and received daily subcutaneous saline administration for the remainder of the study (25 days). Two additional cohorts continued on the 60% HFD (cat. no. 12492; Research Diets, Inc.) and received daily subcutaneous semaglutide administration (0.04 mg/kg; Novo Nordisk) for the duration of the study (26 days). For cohort 1 (control WT n = 8; FGF15INT-KO n = 8), the semaglutide regimen was maintained for 26 days. For cohort 2 (control WT n = 6; FGF15INT-KO n = 9), semaglutide was discontinued after 26 days, and body weight, fat mass, and lean mass were monitored for an additional 28 days. A different cohort of littermate WT and FGF15INT-KO male mice (control WT n = 6; FGF15INT-KO n = 6) was fed an HFD for 19 weeks, and this cohort was used as an HFD control for the analysis of cholesterol, bile acid, and triglyceride levels in liver and cecal content. Body composition was measured using an EchoMRI (Echo Medical Systems). An intraperitoneal glucose tolerance test was performed 22 days after the start of the weight-loss intervention by intraperitoneal injection of 50% dextrose (2 g/kg) in mice fasted for 4 h.

Metabolite, Lipid, and Bile Acid Analyses

Liver and cecal content lipids were extracted using the Lipid Extraction Kit Chloroform Free (Abcam). Total cholesterol (Pointe Scientific), triglyceride (Pointe Scientific), and total bile acid (Total Bile Assay [NBT Method]; GenWay Biotech, Inc.) levels were measured using the extracted lipids. Postprandial plasma obtained at initiation of weight-loss interventions and termination of studies (see above for details) was used to measure insulin (Crystal Chem), total cholesterol (Pointe Scientific), triglyceride (Pointe Scientific), and total bile acid (Total Bile Assay [NBT Method]; GenWay Biotech, Inc.) levels. All assays were performed according to the manufacturers’ instructions. Plasma and liver bile acid compositions were measured in postprandial terminal plasma and liver by the University of Michigan Metabolomics Core, as previously described (19,27).

Bone Parameters

Tissues were fixed in 10% neutral buffered formalin for 24 h and then transferred to Sorenson’s buffer (pH 7.4) for storage. Tibiae were placed in a 19-mm diameter specimen holder and scanned along their entire lengths using a microcomputed tomography (μCT) system (μCT100; Scanco Medical). The scan parameters were as follows: voxel size 10.5 μm3, 70 kVp, 114 μA, aluminum filter 0.5 mm, and integration time 250 ms. Density measurements were calibrated using the manufacturer’s hydroxyapatite phantom. Data analysis was performed using the manufacturer’s evaluation software, with a threshold of 370 mg HA/cm3 for trabecular bone and 700 mg HA/cm3 for cortical bone. Tibiae selected for μCT scanning were decalcified in 14% EDTA for 3 weeks. For histological analysis, paraffin-embedded tissue sections were processed and stained with hematoxylin-eosin.

Quantification of BMAT by Osmium Tetroxide Staining and μCT

Mouse tibiae were decalcified in 14% EDTA for 2 to 3 weeks and then immersed in 1% osmium tetroxide solution (diluted in Sorenson’s buffer; pH 7.4) for 48 h. After osmium tetroxide staining, the bones were scanned using the same μCT protocol described above. A threshold of 400 Gy was applied for BMAT quantification. BMAT volume was normalized to total bone volume and expressed as a percentage.

Statistical Analysis

The statistical analysis for comparisons between the two genotypes for tissue hormone and lipid analysis before weight-loss interventions was performed using an unpaired (two-tailed) Student t test. The statistical analysis comparing four groups was performed using a two-way ANOVA and two-way repeated-measures ANOVA (Tukey multiple-comparisons test). The statistical analysis of plasma and hepatic bile acid composition when comparing two groups was performed using a nonparametric Wilcoxon signed-rank test, and the analysis of four groups was performed using an aligned rank transform ANOVA with Tukey multiple comparisons. Statistical analysis was performed and data graphs were created using GraphPad Prism 10.0 and R software. Illustrations were created with BioRender (biorender.com).

Data and Resource Availability

Data and resources are available on request.

Results

Lean Mass Not Preserved in Mice Lacking Intestinal FGF15 After Diet-Induced Weight Loss

Male WT control and FGF15INT-KO mice were fed a 60% HFD for 22 weeks (Fig. 1A). WT and FGF15INT-KO mice gained comparable body weight, including fat and lean mass (Fig. 1B–D). Rapid weight loss was achieved by switching one cohort of mice back to the regular chow diet (cat. no. 5LOD; PicoLab) along with daily subcutaneous saline administration (25 days) or by continuing the 60% HFD in a second cohort along with daily subcutaneous semaglutide administration (0.04 mg/kg; Novo Nordisk) for the duration of the study (26 days) (Fig. 1A). WT mice switched to a chow diet achieved greater weight loss compared with WT mice receiving an HFD plus semaglutide, but not FGF15INT-KO mice receiving an HFD plus semaglutide (Fig. 1E). WT mice switched to a chow diet lost more fat mass and less lean mass than FGF15INT-KO mice (Fig. 1F and G). These results were comparable when the change was calculated as a percentage difference (Supplementary Fig. 1A–D). Overall, mice switched to a chow diet achieved greater weight loss, losing more fat mass and less lean mass than those treated with semaglutide while fed an HFD (Fig. 1F and G).

Figure 1.

Mouse study schematic shows wild type and intestinal-derived fibroblast growth factor 15 knockout groups fed a sixty percent high-fat diet for twenty-two weeks, then given chow with saline for twenty-five days or a high-fat diet with semaglutide zero point zero four milligram per kilogram daily for twenty-six days. Line plots show increases in body weight, fat mass, and lean mass with a high-fat diet. Scatter plots show reductions in body weight and fat mass, and changes in lean mass, following treatments.

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Lean mass is not preserved in FGF15INT-KO mice after diet-induced weight loss. A: Experimental design. B–D: Body weight (B), fat mass (C), and lean mass (D) of male FGF15INT-KO mice and WT littermate controls fed a 60% HFD for 22 weeks. E–G: Changes in body weight (E), fat mass (F), and lean mass (G) after rapid weight loss induced by either switch from HFD to standard chow diet (saline) or HFD maintenance with daily semaglutide (0.04 mg/kg). Data are shown as mean ± SEM. FF, flox/flox. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by two-way ANOVA (Tukey).

Semaglutide Induced Comparable Weight Loss and Weight Recovery Post–Treatment Cessation in HFD-Fed WT and FGF15INT-KO Mice

Male WT control and FGF15INT-KO mice were fed a 60% HFD before undergoing daily subcutaneous semaglutide administration for 26 days (0.04 mg/kg; Novo Nordisk) (Fig. 2A). Body weight and composition were monitored for 28 days after discontinuation of semaglutide. Mice were fed an HFD for the duration of the study (Fig. 2A). Both genotypes showed similar body weight, fat mass, and lean mass loss during semaglutide-induced weight loss and postsemaglutide regain (Fig. 2B–E). These results were comparable when the change was calculated as a percentage difference (Supplementary Fig. 2A–D). Although FGF15INT-KO mice lost a greater percentage of their baseline weight, primarily due to reduced adiposity, both genotypes had comparable weight, fat, and lean mass regain by the end of the study. Importantly, when semaglutide was discontinued, body weight, fat mass, and lean mass returned to their baseline (pretreatment) levels.

Figure 2.

Mouse study schematic shows wild type and intestinal-derived fibroblast growth factor 15 knockout groups treated with sixty per cent high-fat diet plus semaglutide zero point zero four milligram per kilogram daily for twenty-six days, then semaglutide stops and high-fat diet continues for twenty-eight days. Line plots show body weight, fat mass, and lean mass decrease during treatment and increase after stopping semaglutide across time points zero to twenty-eight days.

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Semaglutide reduces body weight, fat, and lean mass, but these returned to baseline levels after semaglutide treatment. A: Experimental design. B–D: Changes in body weight (B), fat mass (C), and lean mass (D) after rapid weight loss induced by daily semaglutide (0.04 mg/kg) for 26 days and recovery period of 28 days with no semaglutide treatment. Data are shown as mean ± SEM. FF, flox/flox. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by two-way repeated-measures ANOVA (Tukey).

Changes in Bone and BMAT Parameters Depended on Diet, Weight-Loss Intervention, and Intestinal FGF15

Previous work by our laboratory has shown that intestinal FGF15 does not regulate trabecular or cortical bone volume fraction or trabecular bone mineral density (BMD) under standard chow and obesogenic diets (19); however, it is required to maintain bone mass after VSG (27). In the current study, rapid weight loss induced by semaglutide compared with a chow diet led to loss of trabecular bone parameters in WT mice, but not in FGF15INT-KO mice. Specifically, weight loss induced by semaglutide led to decreased trabecular bone volume fraction and trabecular BMD, but not trabecular connective density, in WT mice (Fig. 3A–D). Thickness of the trabecular bone was decreased in both WT and FGF15INT-KO mice treated with semaglutide compared with WT mice fed a chow diet (Fig. 3E). Trabecular number and spacing between trabeculae were comparable between the groups (Fig. 3F and G). Cortical bone area, BMD, and thickness remained comparable between the groups (Fig. 3H–K). Both regulated BMAT in proximal tibia and constitutive BMAT in distal tibia were increased in HFD-fed WT mice treated with semaglutide, but not FGF15INT-KO mice (representative images in Fig. 3L–O). It is worth noting that the reduction in trabecular bone and increase of BMAT in semaglutide-treated WT HFD-fed mice may be partially attributable to HFD feeding (29); however, the distinct responses in FGF15INT-KO mice suggest that intestinal FGF15 or FGF15-mediated response is necessary for skeletal remodeling and BMAT under HFD and semaglutide treatment conditions.

Figure 3.

Panels show tibia bone analysis in wild-type and intestinal-derived fibroblast growth factor 15 knockout mice under chow or high-fat diet with semaglutide. Micro computed tomography images and histology sections of proximal and distal tibiae are presented. Bar plots report trabecular bone volume fraction, bone mineral density, connectivity density, thickness, number, spacing, cortical area, density, and thickness, and marrow adipose tissue percentages with group comparisons and significance markers.

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Changes in bone parameters depend on weight loss intervention and intestinal FGF15. A: Three-dimensional images of trabecular (Tb) bone. B–G: Tb bone volume fraction (BV/total volume [TV]) (B), BMD (C), bone connective density (Conn Des) (D), number (E), bone thickness (Th) (F), and spacing between trabeculae (Sp) (G). H: Three-dimensional images of midcortical (Ct) bone. I–K: Ct bone area (BA/TA) (I), BMD (J), and Th (K). L and M: Tibial BMAT was visualized by osmium staining; representative sections from proximal (L) and distal (M) tibiae were stained with hematoxylin-eosin. N and O: Tibial BMAT was quantified relative to TV after osmium staining in regulated BMAT (rBMAT) (N) and constitutive BMAT (cBMAT) (O). Data are shown as mean ± SEM. *P < 0.05, **P < 0.01 by two-way ANOVA (Tukey).

Semaglutide Improved Glucose Tolerance in HFD-Fed Mice Regardless of Genotype

WT and FGF15INT-KO mice with semaglutide-induced rapid weight loss had better glucose tolerance compared with mice with chow diet–induced weight loss (Fig. 4A). In particular, FGF15INT-KO mice with semaglutide-induced rapid weight loss showed a trend toward greater improvement in glucose tolerance compared with FGF15INT-KO mice switched to a chow diet (Fig. 4B). Before weight loss, WT and FGF15INT-KO HFD-fed mice had comparable postprandial insulin concentrations, as previously shown (Fig. 4C) (19). In accordance with glucose tolerance results, FGF15INT-KO mice with semaglutide-induced rapid weight loss showed a greater decrease in postprandial insulin concentrations than chow-fed FGF15INT-KO mice (Fig. 4D).

Figure 4.

Panels show glucose tolerance test at two grams per kilogram with blood glucose measured from zero to one hundred twenty minutes in wild type and intestinal-derived fibroblast growth factor 15 knockout groups under chow or high-fat diet with semaglutide. Area under the curve values are compared. Plasma insulin levels before weight loss and change in plasma insulin levels across groups are presented with significance markers.

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FGF15INT-KO mice have improved glucose tolerance and decreased insulin levels after semaglutide-induced weight loss compared with diet-induced weight loss. A: Intraperitoneal glucose tolerance test (TT) on day 22 after weight loss intervention. B: Area under the curve (AUC). C: Postprandial plasma insulin levels before weight loss intervention. D: Change in postprandial plasma insulin levels after weight loss intervention by diet (chow) and semaglutide. Data are shown as mean ± SEM. *P < 0.05, ****P < 0.0001 by Student t test (C) or two-way ANOVA (Tukey) (A, B, and D).

Intestinal FGF15 and Weight-Loss Intervention Differentially Regulated Bile Acid Synthesis and Composition

Once released from the ileum, FGF15/19 enters portal venous circulation and travels to the liver, where FGF15/19 binds to its receptor, FGFR4, and represses de novo bile acid synthesis (11) (Fig. 5A). Our previous studies have shown that intestinal FGF15 is necessary for maintaining proper enterohepatic bile acid circulation, and FGF15INT-KO mice have higher plasma (when fed either chow or HFD) and hepatic (only when fed HFD) bile acid levels, as well as higher cecal bile acid levels (when fed either chow or HFD) (19). We have also shown that an HFD does not increase ileal FGF15 expression relative to a chow diet in mice (19), whereas weight loss induced by VSG leads to increased ileal FGF15 expression in mice (27). Our data showed that WT mice undergoing weight loss induced by semaglutide while fed an HFD also had increased ileal expression of FGF15 relative to WT mice that lost weight with a dietary intervention from an HFD to standard chow diet (Fig. 5B). FGF15INT-KO mice that lost weight through a chow diet had increased expression of key bile acid synthesis enzymes Cyp7a1 and Cyp8b1, consistent with a lack of inhibitory signaling by intestinal FGF15 (Fig. 5C and D). In contrast, this increase was lost after weight loss induced by semaglutide while the mice were fed an HFD (Fig. 5C and D).

Figure 5.

Panels show intestine-to-liver signalling via fibroblast growth factor 15 and bile acid synthesis enzymes, cytochrome P 450 family 7 subfamily A member 1 and cytochrome P 450 family 8 subfamily B member 1. Bar plots present gene expression in the ileum and liver, plasma bile acid levels, and hepatic and caecal bile acid content before weight loss and after weight loss with semaglutide. Stacked bars show postprandial plasma and liver bile acid composition across groups with statistical comparisons.

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Semaglutide alters plasma bile acid composition and cecal content bile acid levels. A: Tissue-specific expression of FGF15 and its regulation of hepatic bile acid (BA) synthesis (illustration adapted [19,36]). B: Ileum RNA expression of FGF15. C and D: Hepatic RNA expression of Cyp7a1 (C) and Cyp8b1 (D). E: Postprandial plasma BA levels in WT and FGF15INT-KO HFD-fed mice before weight loss. F: Changes in postprandial plasma BA levels after weight loss. G: Postprandial plasma BA composition in WT and FGF15INT-KO mice before and after weight loss, represented as percentage of whole. H: Hepatic BA levels of WT and FGF15INT-KO HFD-fed mice. I: Hepatic BA levels of WT and FGF15INT-KO chow-fed mice and WT and FGF15INT-KO HFD-fed mice receiving semaglutide. J: Hepatic BA composition in WT and FGF15INT-KO mice before and after weight loss, represented as percentage of whole. K: Cecal content BA levels in WT and FGF15INT-KO HFD-fed mice. L: Cecal content BA levels in WT and FGF15INT-KO chow-fed mice and WT and FGF15INT-KO HFD-fed mice receiving semaglutide. Data are shown as mean ± SEM. WT HFD-fed mice, n = 16; FGF15INT-KO HFD-fed mice, n = 16; WT chow-fed mice receiving saline, n = 8; FGF15INT-KO chow-fed mice receiving saline, n = 8; WT HFD-fed mice receiving semaglutide, n = 8; FGF15INT-KO HFD-fed mice receiving semaglutide, n = 8. CA, cholic acid; CDCA, chenodeoxycholic acid; GCA, glycocholic acid; GDCA, glycodeoxycholic acid; GLCA, glycolithocholic acid; GUDCA, glycoursodeoxycholic acid; Tα/β MCA, tauro-α/β-muricholic acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; THCA, taurohyocholic acid; THDCA, taurohyodeoxycholic acid; TLCA, taurolithocholic acid; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by Student t test (E, H, and K), two-way ANOVA (Tukey) for (B–D, F, I, and L), or nonparametric Wilcoxon signed-rank test and aligned rank-transform ANOVA (with Tukey multiple-comparisons test) (G and J).

Before undergoing rapid weight loss, HFD-fed FGF15INT-KO mice had increased postprandial bile acid levels, similar to what we have shown previously (Fig. 5E) (19). Unlike rapid weight loss induced by VSG, a chow diet and semaglutide did not change postprandial total bile acid levels (Fig. 5F). Bile acid composition analysis revealed that multiple bile acid species differed significantly between various comparisons of WT and FGF15INT-KO mice when fed an HFD, switched to a chow diet, or treated with semaglutide (Fig. 5G). While fed an HFD, FGF15INT-KO mice showed increased levels of taurocholic acid (TCA), glycocholic acid (GCA), α-muricholic acid (αMCA), cholic acid (CA), ursodeoxycholic acid (UDCA), glycodeoxycholic acid (GDCA), and deoxycholic acid (DCA) compared with WT mice, suggesting that genotype strongly affects bile acid metabolism under obesogenic conditions. Comparisons between other groups after rapid weight loss induced by a chow diet or semaglutide consistently showed significant differences in muricholic (MCAs), taurohyocholic (THCA), and deoxycholic (DCA) bile acids, highlighting that both genotype and weight loss treatment modulate bile acid profiles, with semaglutide especially shifting these levels in FGF15INT-KO mice (Fig. 5G). Again, similar to what we have previously shown, HFD-fed FGF15INT-KO mice had elevated hepatic bile acid levels (Fig. 5H) (19). Hepatic bile acid composition showed significant differences in multiple bile acids: tauro-α/β-muricholic acid (Tα/β MCA), tauroursodeoxycholic acid (TUDCA), TCA, ω-muricholic acid (ω-MCA), glycoursodeoxycholic acid (GUDCA), β-muricholic acid (β-MCA), taurodeoxycholic acid (TDCA), CA, and GDCA, with trends for DCA, GCA, and taurohyodeoxycholic acid (THDCA). After weight loss, chow-fed WT and FGF15INT-KO mice had comparable hepatic bile acid levels, whereas FGF15INT-KO mice treated with semaglutide while fed an HFD maintained increased total hepatic bile acids (Fig. 5I) but had comparable hepatic bile acid composition (Fig. 5J).

We further compared plasma and hepatic levels of muricholic, conjugated, and free (unconjugated) bile acids between WT and FGF15INT-KO mice fed an HFD before weight loss. FGF15INT-KO mice with HFD-diet induced obesity had increased plasma conjugated bile acid levels and increased hepatic conjugated, free, and muricholic bile acid levels (Supplementary Fig. 3A and B). We also examined how these subsets of bile acid classes changed in plasma and liver after weight loss induced by switching to a chow diet or semaglutide treatment. For plasma muricholic bile acids, there were significant differences between WT chow-fed and FGF15INT-KO chow-fed groups, between FGF15INT-KO chow-fed and FGF15INT-KO semaglutide-treated mice, and between WT and FGF15INT-KO semaglutide-treated mice, indicating that both genotype and semaglutide have notable effects on muricholic levels (Supplemental Fig. 3A). Additionally, the comparison between WT chow-fed and WT semaglutide-treated animals approached significance, suggesting a possible treatment effect in the WT animals. For circulating free bile acid levels, a significant difference was observed between FGF15INT-KO chow-fed and semaglutide-treated mice, highlighting the impact of semaglutide in the absence of FGF15 (Supplemental Fig. 3A).

HFD-fed FGF15INT-KO mice also had increased cecal content bile acid levels, which remained higher after rapid weight loss induced by a chow diet and semaglutide (Fig. 5K and L). Based on our previously published data, these effects were diet dependent, rather than dependent on semaglutide or weight loss (19). However, our data showed that semaglutide increased cecal bile acid levels in WT mice (Fig. 5L). These findings of increased cecal bile acid levels in chow-fed and semaglutide-treated WT and FGF15INT-KO mice were complemented by a plasma bile acid composition analysis, which showed increased levels of secondary bile acids, such as DCA (Fig. 5G).

Intestinal FGF15 Was Not Necessary for Improvement in Lipid Parameters After Diet-Induced or Pharmacologically Induced Weight Loss

Postprandial plasma cholesterol levels were lower in FGF15INT-KO mice compared with WT mice when fed an HFD, as we previously reported (19) (Fig. 6A). After weight loss, cholesterol levels were more effectively decreased in WT mice switched to a chow diet than in WT and FGF15INT-KO mice that lost weight with semaglutide while fed an HFD (Fig. 6B). Total hepatic cholesterol levels were comparable between WT and FGF15INT-KO mice when fed an HFD and after weight loss induced by switching to a chow diet or being treated with semaglutide while fed an HFD (Fig. 6C and D). Before weight loss, postprandial plasma triglyceride levels were comparable between mice of both genotypes when fed an HFD, as we have shown previously (19) (Fig. 6E). After rapid weight loss, postprandial plasma triglyceride levels were lower in the groups treated with semaglutide than in those switched to a standard chow diet (Fig. 6F). We also observed a trend toward lower postprandial plasma triglyceride levels in FGF15INT-KO chow-fed mice compared with WT chow-fed mice (Fig. 6F). However, although hepatic triglyceride levels were also similar between mice of both genotypes when fed an HFD (Fig. 6G), both WT and FGF15INT-KO mice switched to a standard chow diet had lower hepatic triglyceride levels compared with WT and FGF15INT-KO mice that lost weight with semaglutide while fed an HFD (Fig. 6H and I). Although there were differences in hepatic triglyceride levels, liver weights were comparable between WT and FGF15INT-KO mice that had undergone diet- and semaglutide-induced weight loss (Fig. 6J).

Figure 6.

Panels show plasma cholesterol and triglycerides, and hepatic lipid content in wild-type and intestinal-derived fibroblast growth factor 15 knockout groups before weight loss and after weight loss with semaglutide. Bar plots present plasma cholesterol, change in plasma cholesterol, hepatic total cholesterol, plasma triglycerides, change in plasma triglycerides, and hepatic triglycerides. Liver histology sections show lipid accumulation across groups. Liver weight is compared after weight loss.

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Intestinal FGF15 is not necessary for improvements in lipid parameters after diet- or pharmacologically induced weight loss. A: Postprandial plasma cholesterol levels in WT and FGF15INT-KO HFD-fed mice before weight loss. B: Changes in postprandial plasma cholesterol levels after weight loss. C: Hepatic cholesterol levels in WT and FGF15INT-KO HFD-fed mice. D: Hepatic cholesterol levels in WT and FGF15INT-KO chow-fed mice and WT and FGF15INT-KO HFD-fed mice receiving semaglutide. E: Postprandial plasma triglyceride levels in WT and FGF15INT-KO HFD-fed mice before weight loss. F: Changes in postprandial plasma triglyceride levels after weight loss. G: Hepatic triglyceride levels in WT and FGF15INT-KO HFD-fed mice. H: Hepatic triglyceride levels in WT and FGF15INT-KO chow-fed mice and WT and FGF15INT-KO HFD-fed mice receiving semaglutide. I: Representative sections from respective livers were stained with hematoxylin-eosin. J: Liver weights of WT and FGF15INT-KO chow-fed mice and WT and FGF15INT-KO HFD-fed mice receiving semaglutide. Data are shown as mean ± SEM. WT HFD-fed mice, n = 16; FGF15INT-KO HFD-fed mice, n = 16; WT chow-fed mice receiving saline, n = 8; FGF15INT-KO chow-fed mice receiving saline, n = 8; WT HFD-fed mice receiving semaglutide, n = 8; FGF15INT-KO HFD-fed mice receiving semaglutide, n = 8. *P < 0.05, **P < 0.01by Student t test (A, C, E, and G) or two-way ANOVA (Tukey) (B, D, F, H, and J).

Discussion

VLEDs, bariatric surgery, and pharmacological therapies, such as GLP-1RAs, result in substantial weight loss and reduced adiposity. However, a significant concern with these interventions is the concomitant loss of lean mass after rapid weight loss (3–6). In our study, mice with diet-induced obesity switched to a standard chow diet achieved greater weight loss, with better preservation of lean mass and trabecular bone, than obese mice treated with semaglutide while fed an HFD (Figs. 1 and 3). Notably, the reductions in body weight, fat, and lean mass achieved with semaglutide were fully reversible on discontinuation of treatment, indicating no lasting impact on lean mass (Fig. 2). This finding also underscores the importance of ongoing therapy or lifestyle modifications to maintain weight loss in clinical practice after semaglutide is stopped.

This study aimed to investigate the role of intestine-derived FGF15 in regulating lean mass, blood glucose, bile acid, and lipid parameters during rapid weight loss induced by dietary and pharmacological interventions. Using FGF15INT-KO mice and littermate WT controls with diet-induced obesity, we stimulated rapid weight loss either by 1) switching HFD-fed mice to a standard chow diet for 25 days or 2) administering daily semaglutide while maintaining an HFD. Lean mass was not preserved in mice lacking intestinal FGF15 during diet-induced weight loss; WT mice retained more lean mass than FGF15INT-KO mice when switched from an HFD to a chow diet. During semaglutide-induced rapid weight loss, mice of both genotypes lost similar amounts of body weight, fat mass, and lean mass, which were fully regained after treatment ended. Semaglutide-treated mice had improved glucose tolerance and lower plasma triglycerides, but not plasma cholesterol, compared with mice switched to a chow diet. Changes in bone parameters depended on the type of weight-loss intervention rather than on intestinal FGF15, and semaglutide altered bile acid composition independently of weight loss, whereas improvements in lipid profiles after weight loss were comparable across genotypes.

These findings suggest that gut–muscle communication may play a crucial role in the loss of lean mass that accompanies weight loss. Prior research has demonstrated that pharmacological administration of FGF19 can help restore lean mass in mouse models of glucocorticoid treatment, sarcopenia, and obesity, an effect mediated through FGF15/19 signaling via FGFR4 in muscle (30,31). However, rather than acting directly on muscle, FGF15/19 may influence lean mass after rapid weight loss by altering bile acid levels and composition. Because FGF15/19 is produced by ileal enterocytes, one of its primary functions is the inhibition of new bile acid production in the liver (11). Loss of intestinal FGF15 in mice with HFD-induced obesity resulted in increased plasma and hepatic bile acid levels, particularly conjugated bile acid levels, highlighting the regulatory role of FGF15 in bile acid metabolism (Fig. 5 and Supplementary Fig. 3).

After weight loss with a chow diet or semaglutide treatment, both genotype and treatment significantly influenced plasma concentrations of muricholic and free bile acids, with semaglutide having pronounced effects in FGF15-deficient mice. WT mice treated with semaglutide and FGF15INT-KO mice that had undergone rapid weight loss by a switch to a chow diet or treatment with semaglutide also showed increased levels of cecal bile acid (Fig. 5). These changes were accompanied by an increase in circulating levels of DCA, a secondary bile acid produced in the intestine and mechanistically linked to the maintenance of lean mass. The increase in plasma DCA levels with semaglutide is consistent with human data showing that liraglutide, another GLP-1RA, increases plasma and fecal DCA levels in patients with type 2 diabetes (32). Past studies have shown that DCA can induce skeletal muscle atrophy (33,34). Therefore, changes in bile acid composition, rather than FGF15/19, may represent one mechanistic link to the maintenance of lean mass after weight-loss interventions. However, future studies are required to assess this hypothesis directly. Because DCA is produced by microbial modification in the intestine, the microbiome may also play a role in influencing bile acid composition and ultimately in the regulation of lean tissue. Clinical data have suggested that GLP-1RAs, such as semaglutide, may act as bile acid sequestrants, and our data showing that semaglutide increased the bile acid levels in cecal content support that hypothesis (35). However, semaglutide treatment did not alter circulating total bile acid levels, although it did significantly alter bile acid composition, leaving the mechanism of action unclear. Overall, our findings support the hypothesis that both altered bile acid composition and intestine-derived FGF15 may contribute to the loss of lean mass after rapid weight loss induced by semaglutide. However, future studies are necessary to determine the individual roles and relative contributions of each factor.

Our previous studies showed that baseline BMI and the presence of type 2 diabetes in individuals with obesity may be predictive of baseline FGF19 levels (28). In this study, we aimed to dissect the relationship between FGF15 and type 2 diabetes. Our data suggest that the role of FGF15 in resolving glucose intolerance may not depend on weight loss. Specifically, although mice switched to a chow diet lost more body weight, semaglutide-treated mice showed improved glucose tolerance even while fed an HFD (Fig. 4). The interactions between FGF15/19, body weight, and glucose tolerance seem complex and likely involve additional factors, such as changes in lipid parameters. For example, semaglutide-treated mice fed an HFD had a greater reduction in circulating triglyceride levels, whereas chow diet–induced weight loss produced a larger decrease in hepatic triglyceride levels (Fig. 6). Future studies will focus on the roles of lipid load and FGF15/19 in regulating blood glucose, body weight, and composition in the context of obesity and rapid weight loss.

The current study has several limitations and suggests important avenues for future research. Notably, weight loss achieved through pharmaceutical interventions is most effective when combined with dietary modifications and sustained physical activity. In this study, mice were either switched from an HFD to a standard chow diet (diet modification alone) or fed an HFD while receiving semaglutide (pharmaceutical intervention alone). The latter approach, continuing an unhealthy diet while relying solely on medication, is not recommended in clinical practice, because dietary changes are necessary for optimal outcomes. The standard chow diet is rich in fiber, and consequent changes in the microbiome, secondary bile acids, and gut function may have affected the preservation of lean mass after rapid weight loss. Therefore, future studies should evaluate the combined effects of dietary and pharmacological interventions. The results presented here suggest that changes in bile acid composition and/or intestinal FGF15 may contribute to lean mass loss after rapid weight loss induced by semaglutide; however, more research is needed to elucidate their specific effects. This study assessed only two weight-loss interventions; future work should include weight-matched, pair-fed control groups to account for the effects of reduced calorie intake and weight loss independent of the drug’s action. Additionally, these studies were restricted to male mice, and future studies will be needed to assess these effects in females. Lastly, future studies will need to evaluate the function of lean mass in addition to the changes in lean mass after interventions.

In summary, these findings highlight the complexity of metabolic regulation during rapid weight loss, revealing that both the gut-derived hormone FGF15 and pharmacological treatments, such as semaglutide, play distinct and complementary roles. Although intestinal FGF15 or FGF15-mediated changes in bile acid metabolism may help preserve lean mass during dietary interventions, semaglutide provides broader metabolic benefits, including improved glucose tolerance and lipid profiles, regardless of FGF15 status. These findings underscore the importance of tailoring weight-loss strategies to individual metabolic needs, suggesting that combining dietary and pharmacological approaches could optimize both body composition and metabolic health.

This article contains supplementary material online at https://doi.org/10.2337/figshare.31626184.

Article Information

Duality of Interest. R.J.S. has received research support from Fractyl, AstraZeneca, Congruence Therapeutics, Eli Lilly, Diasome, and Amgen; has been a paid consultant for Novo Nordisk, Eli Lilly, CinRx, Crinetics, Amgen, Helicore, Gallant, General Medicines, AbbVie, Protagonist Therapeutics, Aardvark, Zealand, and Nuanced Health; and has equity in Nuanced Health, Coronation Bio, Eccogene, Fractyl, and Rewind. O.A.M. has received grant support from Regeneron, Dicerna, CombiGene AB, and Rejuvenate Bio. J.H.S. is a paid employee of Amgen. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. N.B.-K., G.M., Z.L., and J.H.S. performed the experiments and analyzed the results. N.B.-K. and R.J.S. conceived and designed the study. J.W. analyzed results and generated graphs. A.M., R.W.O., and O.A.M. helped with data interpretation and discussion. R.J.S. provided final approval of the submitted manuscript. All authors edited the manuscript. R.J.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Statement

This research was supported by the Department of Veterans Affairs grants IK2BX005715 (N.B.-K.) and I01CX001811 (R.W.O.). This study was supported by National Institutes of Health (NIH)–funded Michigan Nutrition Obesity Research Center grant P30DK089503 (R.J.S.); Michigan Institute for Clinical and Health Research grant UL1TR002240 (N.B.-K.), and NIH awards R01DK133140 (R.J.S.), R01DK137798 and R01DK125513 (O.A.M.), R25DK141426 (G.M.), and P20GM121301 (Z.L.).

Supporting information

Supplementary Material
db250466_supp.pdf (2.3MB, pdf)

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Supplementary Materials

Supplementary Material
db250466_supp.pdf (2.3MB, pdf)

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