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Adipose-specific HuR deletion protects against high-fat diet-induced obesity in mice through upregulating Ucp1 expression

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SUBMITTER: Fan X

PROVIDER: S-EPMC12376737 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature

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Project description:Purpose: To investigate alterations in subcutaneous white adipose gene expression induced by genetic AMPK activation in vivo, in mice fed a chow or a high-fat diet. Methods: Subcutaneous white adipose tissue mRNA profiles of wild-type transgenic (WT-Tg) mice and mice expressing a gain-of-function AMPK mutant gamma1 subunit (D316A-Tg) were generated by deep sequencing. Results: RNA sequencing revealed over 3000 differentially expressed genes between WT-Tg and D316A-Tg subcutaneous white adipose tissue (WATsc) from mice fed a high fat diet (HFD), of which many were classified as 'skeletal muscle-associated'. Interestingly, uncoupling protein 1 (UCP1), associated with 'beige' adipocyte formation in WATsc, was not differentially expressed. On a chow diet, many differentially expressed genes were also identified, with gene ontology analysis identifiying glycolysis, TCA cycle and brown fat differentiation as highly enriched; key features of brown adipocyte identity. HFD-associated skeletal-muscle associated gene expression was either not significantly altered, or significantly down-regulated on a chow diet, indicating a diet-induced gene signature in D316A-Tg WATsc. Conclusions: Our study revealed gene signatures indicative of brown adipocyte development on a chow diet, where no overt metabolic phenotype was observed in gain-of-function animals. When fed a HFD, WATsc from D316A-Tg mice displayed a muscle-like gene signature, expressing key components of creatine and calcium thermogenic cycles including Ckmt2 (creatine kinase, mitochondrial 2) Atp2a1 (SERCA1-sarco/endoplasmic reticulum ATPase 1) and ryr1 (ryanodine receptor 1). UCP1 expression was not altered between WT-Tg and D316A-Tg mice fed a HFD. Our findings suggest a novel role for AMPK in the regulation of white adipocyte identity and a potentially novel cell population that, when metabolically challenged, preferrentially utilise muscle-like thermogenic futile cycles independent of UCP1 to mediate whole organism energy expenditure.

Project description:ABSTRACT OBJECTIVE: Genome Wide Association Studies (GWAS) in humans, dogs, and livestock have uncovered genes which may play a role in metabolism. However, functional analysis is required to link the metabolic phenotype with the associated gene. Here we identified the Ligand Dependent Corepressor-Like (LCoRL) as a potential metabolic regulator. METHOD: We used CRISPR/Cas9 approaches in mice to generate a Lcorl null allele (Lcorl-/-). We characterized Lcorl-/- mice by assessing body weight, body composition, food intake, and glucose homeostasis as well as assessing transcriptional changes in Lcorl-/- livers by RNA-sequencing. Finally, we challenged mice with a 60% high fat diet (HFD) and a treadmill exercise stress test. RESULTS: Mice homozygous for loss of Lcorl are viable and fertile. However, Lcorl-/- pups show stunted postnatal growth for the first few weeks of life. This is followed by a catchup growth, such that, Lcorl-/- mice are indistinguishable from wildtype littermates by 7-9 weeks of age. Three-week-old mice show reduced circulating insulin like growth factor-1 (IGF-1) levels without a change in pituitary Growth hormone (Gh) mRNA levels. Interestingly, Lcorl-/- mice remain lean compared to wildtype littermates as they age. This is associated with a decrease in daily food intake. Additionally, Lcorl-/- mice show no change in energy expenditure; however, Lcorl-/- mice show a greater amplitude of their respiratory exchange ratio (RER) compared to controls, suggesting differential usage of fat and carbohydrates across the light/dark cycle. This altered RER may result from the reduction in day-time food intake or disrupted mobilization of fat and carbohydrate stores. Consistent with enhanced metabolic health, Lcorl-/- mice also show improved glucose tolerance and insulin sensitivity. Finally, Lcorl-/- mice are protected against a 60% high fat diet challenge and show reduced exercise capacity in a stress test. CONCLUSION: This phenotypic characterization of the Lcorl-/- mouse reveals that LCoRL is a causal gene resulting in the changes in metabolism seen in GWAS in humans and livestock and provides novel mechanistic insights of a gene important in human disease and economically valuable traits in livestock.

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Adipose-specific HuR deletion protects against high-fat diet-induced obesity in mice through upregulating Ucp1 expression

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