2. Academic Validation
  3. Exclusive Breastfeeding Drives AMPK-Dependent Thermogenic Memory in BAT and Promotes Long-Term Metabolic Benefits in Offspring

Exclusive Breastfeeding Drives AMPK-Dependent Thermogenic Memory in BAT and Promotes Long-Term Metabolic Benefits in Offspring

  • Adv Sci (Weinh). 2025 Dec 19:e08956. doi: 10.1002/advs.202508956.
Ningxi Wu 1 2,  Anwen Yin 3,  Xiang Yu 4,  Mingxin Wang 1,  Jiahui Zhang 1,  Kerong Liu 5,  Yutong Hou 4,  Minkai Cao 6,  Yiting Zhang 1,  Xiaoxiao Zhang 1,  Yao Gao 7,  Xirong Guo 8,  Le Zhang 2,  Yun Li 1
Affiliations

Affiliations

  • 1 Department of Pediatric Laboratory, Affiliated Children's Hospital of Jiangnan University, Wuxi Children's Hospital, Wuxi Key Laboratory of Genetic and Metabolic Diseases in Children, Wuxi, Jiangsu, 214023, China.
  • 2 Department of Neonatology, Affiliated Children's Hospital of Jiangnan University, Wuxi Children's Hospital, Wuxi, Jiangsu, 214023, China.
  • 3 Department of Cardiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
  • 4 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 5 Department of Endocrinology, Affiliated Children's Hospital of Jiangnan University, Wuxi Children's Hospital, Wuxi, Jiangsu, 214023, China.
  • 6 Department of Obstetrics and Gynecology, Affiliated Women's Hospital of Jiangnan University, Wuxi Maternity and Child Health Care Hospital, Wuxi, Jiangsu, 214002, China.
  • 7 Department of Endocrinology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210008, China.
  • 8 Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
PMID: 41417620 DOI: 10.1002/advs.202508956
Abstract

Exclusive breastfeeding reduces the risk of childhood obesity, potentially through metabolic programming of adipose tissue during lactation. However, the underlying mechanisms remain unclear. Using a mouse model, it is shown that mixed formula feeding disrupts brown adipose tissue (BAT) morphology, mitochondrial integrity, and thermogenic capacity, resulting in greater fat accumulation and glucose intolerance after weaning under a high-fat diet. By contrast, BAT from exclusively breastfed mice preserved enhanced thermogenic function for up to 12 weeks after transplantation into recipient mice. Transcriptomic analysis revealed that AMPK activation is sustained in BAT from exclusively breastfed mice but markedly diminished in mixed-fed counterparts. Pharmacological inhibition of AMPK abolished the long-term metabolic benefits conferred by exclusive breastfeeding. Mechanistically, breast milk-derived extracellular vesicles enriched in miR-125a-5p enhanced AMPK signaling by targeting HIF1AN. AMPK-induced α-ketoglutarate (αKG) production proved essential for BAT development and thermogenesis, and αKG supplementation rescued impaired BAT function in mixed-fed mice. In conclusion, exclusive breastfeeding imprints a thermogenic memory in BAT via the HIF1AN/AMPK/αKG signaling axis, thereby conferring long-term metabolic protection to offspring.

Keywords

AMPK; breastfeeding; brown adipose tissue; childhood obesity; α‐ketoglutarate.

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