时间标签：数据日期 2026-10-31 · 生成时间 2026-11-01 05:30（Asia/Shanghai）｜ 检索窗口 PubMed edat 2026/10/28–2026/10/31 ｜ 情报发生日期 2026-10-31
研究问题
Subsequent genetic and pharmacological analyses questioned whether these effects reflected direct inhibition of p38: acute insulin‐stimulated glucose uptake was preserved in adipose tissue and skeletal muscle from p38β‐deficient mice, while the effect of the pharmacological inhibition of p38α/β SB203580 [] on glucose transport was shown to vary independently of its inhibition of p38 activity [].；Thus, these studies did not establish a clear member‐specific role for p38 in glucose transport and did not address whether p38β contributes to the maintenance of adipocyte insulin signaling during prolonged nutritional stress.；Their substrate preferences are not absolute, however, and depend on the stimulus, cellular environment, and relative abundance of the individual kinases [, , ].
方法
Exclusion criteria included alcohol use disorder or excessive alcohol intake (> 30 g/day in men and > 20 g/day in women) and chronic hepatitis B or C.；The study was approved by the Ethics Committee of the University Hospital of Salamanca, and all participants provided written informed consent.；To generate tissue‐specific knockout mice, we used the Cre‐LoxP system.；To reduce the number of LoxP sequence recombinations needed and achieve a better depletion of Mkk3 gene, we crossed these mice with full knockout Mkk3 mice (Mkk3 − / −), obtaining Fabp4‐Cre+Mkk3f/ − mice (FKO mice).
核心结论
Stress‐kinase pathways can have beneficial or detrimental effects in adipose tissue depending on the kinase, cell type, and metabolic context [].；To investigate whether the MKK3 pathway is altered in human obesity, we analyzed visceral adipose tissue and circulating metabolic markers in patients undergoing bariatric surgery and in a lower‐BMI surgical comparison group undergoing cholecystectomy.；As expected, patients with obesity displayed higher circulating insulin, C‐peptide, and leptin levels and lower adiponectin levels than the cholecystectomy group (Figure and Table ). ‖ 结论：Overall, our results support a model in which early induction of adipocyte MKK3 during obesity helps preserve insulin responsiveness by engaging p38β and restraining p70S6K‐dependent inhibitory phosphorylation of IRS1.
局限
During energetic stress, p38β activates PRAK/MK5, which directly phosphorylates Rheb at Ser130, impairing its nucleotide‐binding capacity and thereby limiting Rheb‐dependent mTORC1 activation and S6K1 phosphorylation.；Additional mechanisms upstream of Akt cannot be excluded. p38 family members have been shown to regulate PI3K signaling independently of mTORC1.；Several limitations should be considered.
对本项目的价值
★☆☆☆☆ 代谢轴既干预敏感性最高，也是老药新用供给最充足的来源。最大样本量约 4,708,671。
全文来源
PMC JATS 全文（正文 51,756 字符，已过标题/DOI 逐字归属校验）
原文题录
- 英文标题：An Adipocyte MKK3-p38β Axis Preserves Insulin Responsiveness in Mice and Is Reciprocally Altered in Human Obesity.
- 期刊与标识：Adv Sci (Weinh) · PMID 42952173 · DOI 10.1002/advs.202520388
A 级证据分级：A 级（同行评议人体研究）
本文属人体研究证据，但需注意：观察性或小样本干预的结论不等于已证实临床获益；效应量与长期安全性仍需更大规模、更长随访的试验验证。
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