Early nutrition impacts later setmelanotide treatment of obesity in mice

To the Editor: Early malnutrition can impact development, leading to the question of whether this may reduce the efficacy of obesity treatments in adulthood. Preclinical models have shown a direct impact of maternal diet on the melanocortin system in the offspring (1). In this study, we investigated whether overnutrition in early development coupled to adult obesity leads to a reduced response to the melanocortin system agonist setmelanotide, in adulthood. We hypothesized that early overnutrition alters the physiological responses to treatments targeting the melanocortin system, particularly in managing adult obesity. To test this hypothesis, we employed a model of maternal high-fat diet (mHFD) during lactation (2). The control mothers were fed with a matched control diet (mCD). The offspring received a secondary metabolic challenge with 60% HFD (aHFD) at 4 months of age to establish a severely obese phenotype in adulthood (Figure 1A and Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.197382DS1), similar to previous studies of setmelanotide (3). This allowed for the study of adult-onset obesity as well as early maternal overnutrition. At 11 months of age, an osmotic minipump was implanted subcutaneously to deliver either the α-MSH mimetic, setmelanotide, or saline (vehicle) for 4 weeks. Daily body weight measurements were taken during the initial 2 weeks of setmelanotide treatment (Figure 1B). The 2 diet groups are defined as follows: CH represents mCD+aHFD, and HH represents mHFD+aHFD.

Figure 1

Maternal overnutrition influences the response to setmelanotide treatment in adult obese mice. (A) Study design, diet groups, and timeline for treatment. (B) Osmotic minipump implantation in adult offspring. (C) Z-score of body weight change in setmelanotide-treated males and females standardized to vehicle controls for 2 weeks of treatment; repeated measures 2-way ANOVA. CH setmelanotide females (n = 12), HH setmelanotide females (n = 14), CH setmelanotide males (n = 16), HH setmelanotide males (n = 11). (D) Body weight loss plotted as percentage body weight change after a 16-hour fast. (E) Fasting blood glucose levels. (F) Fasting insulin levels. (G) HOMA-IR measured in all groups. Analyses in D–G were performed using a 3-way ANOVA with Šídák’s post hoc testing. See Supporting Data Values file for statistical details. Squares represent males and open circles represent females; dark blue shading represents the CH treatment group and orange represents the HH treatment group. A and B were designed with BioRender. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

In line with previous setmelanotide studies (3–5), all setmelanotide-treated animals lost body weight across the treatment period versus their respective controls (Figure 1C and Supplemental Figure 1, B–E). Analysis of setmelanotide-treated groups uncovered a significant sex effect in body weight loss, with females resulting in significantly less (P_sex < 0.001) body weight loss than males (Figure 1C and Supporting Data Values file). Strikingly, maternal diet significantly impaired the effectiveness of setmelanotide in reducing body weight (Figure 1C; ♂ P_mDiet = 0.039, ♀ P_mDiet = 0.019).

To further test whether setmelanotide’s overt effects on body weight loss and the interaction with maternal diet were due to changes in glucose metabolism, animals were exposed to a 16-hour fasting period after 4 weeks of treatment. Setmelanotide treatment significantly exacerbated body weight loss due to fasting, regardless of the maternal diet group. Furthermore, a significant interaction of the setmelanotide treatment response with the sex of the animals was also noted, with a more pronounced body weight loss in CH and HH females relative to vehicle (Figure 1D). Overall, setmelanotide treatment resulted in reduced fasting blood glucose, irrespective of mDiet and sex (Figure 1E). A significant effect of maternal diet was uncovered in fasting insulin levels (Figure 1F), without further interaction with treatment and sex. Fasting insulin however showed significant effects of maternal diet, sex, and treatment. A significant interaction effect of sex and treatment was also detected. Post hoc analysis uncovered a significant reduction in HH male insulin levels due to setmelanotide treatment (P = 0.0432). (Figure 1F). HOMA-IR analysis displayed overall independent main effects of sex and setmelanotide treatment (Figure 1G).

Setmelanotide has shown greater than 10% reductions in body weight in genetic forms of obesity leading to significant clinical benefits (6). However, many randomized clinical studies using (neuro)peptide mimetics report a significant percentage of participants who do not sufficiently respond to the intervention (7, 8). Here, we provide preclinical evidence that the early nutritional environment may disrupt responses to therapeutics targeting the melanocortin system, resulting in impaired weight loss during treatment. This is supported by preclinical models of maternal obesity showing links to altered melanocortin system development (1), reviewed in Chong and Dearden (9). However, further analysis of the specific acute activation of these neurocircuits is warranted. We detected the impact of maternal diet on fasting insulin measurements only, which may be due to prolonged HFD masking the maternal diet contribution. Shorter diet interventions are warranted. We also uncovered an intriguing finding of pronounced fasting-induced body weight loss in setmelanotide-treated females that may be due, in part, to documented sexual dimorphism in melanocortin circuits (10). These data underscore the need to incorporate early-life metabolic factors into treatment regimens. It may explain the lack of responsiveness in clinical trials for setmelanotide and similar therapies. Further studies should explore how early nutrition influences responsiveness to treatments, potentially improving therapeutic strategies.

For detailed methods, information regarding sex as a biological variable, statistics, study approval, and author contributions, see the supplemental materials.

Manuscript information

Conflict of interest. The authors have declared that no conflict of interest exists.

Funding. This study was supported by the following:

• Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) under Germany´s Excellence Strategy—EXC-2049—390688087 (NeuroCure) to RNL.
• German Center for Diabetes Research (82DZD03D2Y, 82DZD03D03, and 82DZD03I04) to RNL.
• Leibniz Association through the Leibniz Competition Best Minds Grant ‘BAByMIND’ (J99/2020) to RNL.

Supplemental material

View Supplemental data

View Supporting data values

Footnotes

Copyright: © 2026, Baidoe-Ansah et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: JCI Insight. 2026;11(21):e197382. https://doi.org/10.1172/jci.insight.197382.

Address for correspondence. Rachel Lippert, DIfE, Arthur-Schuenert-Allee 114-116 Nuthetal, Germany 14558. Email: rachel.lippert@dife.de or rachel.lippert@ovgu.de.

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