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Cardiovascular Disease and Adiposity / Adipokines, Inflammation, and Metabolic Diseases · Journal article
Cell Communication and Signaling · September 10, 2026
Raises a question worth testing. It does not answer one.
This mechanistic study identifies UCP1 neddylation at lysine residues K138 and K237 as a dual regulatory mechanism controlling mitophagy and proteasomal degradation in white adipocytes, with proof-of-concept in mouse models. Neddylation inhibition via MLN4924 promoted browning and improved metabolism in wild-type mice but not UCP1-knockout animals, suggesting UCP1-dependency; however, the work remains preclinical and does not establish human efficacy or safety.
Mechanistic study combining in vitro cell differentiation, site-directed mutagenesis, immunoprecipitation, electron microscopy, and HFD-induced obese mouse models with randomization. 3T3-L1 white adipocyte cell line; genetically modified and wild-type mice (Ucp1+/+ and Ucp1−/−) fed high-fat diet to induce obesity. Intervention: Neddylation inhibition via MLN4924 treatment in mice; site-directed lysine mutations (K138, K237) in UCP1; MDM2 knockdown. Compared with: Vehicle control in mice; wild-type versus UCP1-knockout genotypes.
UCP1 neddylation at K138 by MDM2 facilitates NIX-mediated mitophagy through UCP1–NIX interaction UCP1 neddylation at K237 by MDM2 promotes UCP1 proteasomal degradation MLN4924 treatment reduced body weight, enhanced thermogenic capacity, and improved energy metabolism in Ucp1+/+ mice
No long-term safety or pharmacokinetic data for MLN4924 in the obesity context
The findings are preclinical and mechanistic; they do not yet support clinical recommendations. The work identifies a novel post-translational target (UCP1 neddylation) and suggests neddylation inhibitors merit investigation in obesity, but human efficacy, safety, dosing, and long-term effects remain unknown.
Mechanistic study in cell culture and animal models identifying a post-translational regulatory pathway; lacks human data, hard clinical outcomes, or phase clinical trial evidence needed to support clinical translation.
As stated by the source record.
Quoted from the source exactly as published.
The findings are preclinical and mechanistic; they do not yet support clinical recommendations. The work identifies a novel post-translational target (UCP1 neddylation) and suggests neddylation inhibitors merit investigation in obesity, but human efficacy, safety, dosing, and long-term effects remain unknown.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Abstract Background Adipocyte browning contributes to energy homeostasis and represents a promising strategy for obesity treatment. Uncoupling protein 1 (UCP1), a well-established marker of beige adipocytes, has been regarded as a key effector that promotes energy expenditure and improves glucose metabolism. However, the observations that Ucp1 -knockout ( Ucp1 −/− ) mice exhibit unexpected resistance to obesity and increased beige adipocyte-like features in white adipose tissue (WAT) have rendered the precise role of UCP1 in browning controversial. We investigated the role of UCP1 neddylation in white adipocytes and its relevance in high-fat diet (HFD)-induced obesity. Methods The impact of neddylation inhibition on 3T3-L1 cells during white adipocyte differentiation was assessed by evaluating lipid accumulation, browning markers, and mitochondrial function. UCP1 neddylation and its downstream regulation of ubiquitination and mitophagy were examined with co-immunoprecipitation and transmission electron microscopy (TEM). Site-specific UCP1 lysine mutants and murine double minute 2 ( MDM2 ) knockdown models were further used to identify the neddylation sites and the responsible E3 ligase. Functional validation was conducted in HFD-induced obese Ucp1 +/+ and Ucp1 −/− mice. Each genotype was randomized to receive either MLN4924 or vehicle. Assessments included histological evaluation, glucose and insulin tolerance tests, and metabolic analysis using the Comprehensive Lab Animal Monitoring System (CLAMS). Results Neddylation of UCP1 at K138 by MDM2 facilitates NIX-mediated mitophagy through the interaction between UCP1 and NIX. At a different site, neddylation of UCP1 at K237 by MDM2 promotes UCP1 proteasomal degradation. Blockade of neddylation induces beige adipocyte features in white adipocytes, characterized by UCP1 accumulation and increased mitochondrial content. Consistently, MLN4924 treatment reduced body weight, enhanced thermogenic capacity, and improved energy metabolism in Ucp1 +/+ mice. These treatment effects were not observed in Ucp1 −/− mice, indicating a UCP1-dependent pathway. Conclusions This study identifies UCP1 neddylation as a dual regulatory mechanism controlling UCP1 turnover and mitophagy in white adipocytes. These findings provide a post-translational explanation for the paradoxical metabolic phenotypes associated with altered UCP1. Targeting UCP1 neddylation promotes adipocyte browning and improves energy metabolism, representing a potential therapeutic strategy for obesity.
Taken from the source record, never inferred. Follow any of these and new work involving them reaches your briefing.