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Receptor Mechanisms and Signaling · Journal article
Nature Communications · September 8, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is a preclinical mechanistic study demonstrating that CNIH4 coordinates β-adrenergic receptor trafficking in skeletal muscle and adipose tissue to support exercise-induced metabolic adaptation in male mice. Loss of CNIH4 impairs glucose utilization, exercise capacity, and thermogenesis; pharmacological β-adrenergic activation partially rescues some defects. The findings are restricted to mice and do not yet establish human relevance or clinical utility.
Preclinical mechanistic study using genetic knockouts in male mice. Male mice with CNIH4 deletions in all tissues or skeletal muscle specifically; human skeletal muscle biopsies post-resistance training. Intervention: Genetic deletion of CNIH4; pharmacological β2- or β3-adrenergic receptor activation. Compared with: Wild-type or control mice; untreated knockout mice.
CNIH4 expression increases in human and mouse skeletal muscle after resistance training Loss of CNIH4 in all tissues or skeletal muscle impairs β2-adrenergic receptor trafficking, causing exercise-induced hyperglycemia and defective glucose use Loss of CNIH4 worsens diet-induced obesity and weakens β3-adrenergic receptor signaling in adipose tissue
Quantitative effect sizes (e.g., magnitude of hyperglycemia, obesity worsening, or pharmacological rescue) not specified Pharmacological activation of β2- or β3-adrenergic receptors partially restores glucose or adipose defects
This work identifies CNIH4 as a potential target for enhancing metabolic adaptation to exercise, but human studies and clinical trials are needed to establish relevance for glucose metabolism, obesity, or exercise performance in people.
Mechanistic study in male mice showing CNIH4 regulates β-adrenergic receptor trafficking and metabolic outcomes; lacks human data, clinical endpoints, or comparison to established interventions.
As stated by the source record.
This work identifies CNIH4 as a potential target for enhancing metabolic adaptation to exercise, but human studies and clinical trials are needed to establish relevance for glucose metabolism, obesity, or exercise performance in people.
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Exercise improves glucose and lipid metabolism by remodeling skeletal muscle and adipose tissue, processes that depend on beta-adrenergic receptor signaling. How receptor trafficking and activation are coordinated across tissues remains unclear. Here we show that Cornichon homolog 4 controls beta-adrenergic receptor localization and activity in metabolic tissues. Cornichon homolog 4 expression increases in human and mouse skeletal muscle after resistance training. Loss of Cornichon homolog 4 in all tissues or skeletal muscle impairs beta2-adrenergic receptor trafficking and causes exercise-induced hyperglycemia and defective glucose use. Its loss also worsens diet-induced obesity. In adipose tissue, loss of Cornichon homolog 4 weakens beta3-adrenergic receptor signaling, thermogenesis and exercise-induced lipolysis. Pharmacological activation of beta2- or beta3-adrenergic receptors partially restores glucose or adipose defects. Mechanistically, Cornichon homolog 4 links adrenergic receptor signaling to extracellular matrix gene expression and Smad signaling. These findings identify Cornichon homolog 4 as a coordinator of metabolic adaptation. Liu et al. show in male mice that CNIH4 helps adrenaline receptors reach cell surfaces, supporting skeletal muscle glucose use and uphill exercise performance, while promoting brown fat breakdown and heat production in adipose tissue.
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