2. Academic Validation
  3. A catecholamine-independent pathway controlling adaptive adipocyte lipolysis

A catecholamine-independent pathway controlling adaptive adipocyte lipolysis

  • Nat Metab. 2026 Jan;8(1):96-115. doi: 10.1038/s42255-025-01424-5.
Xiao Zhang # 1 2,  Sreejith S Panicker # 1 2,  Jordan M Bollinger 1 2,  Anurag Majumdar 1,  Rami Kheireddine 1 3,  Lila F Dabill 1 2,  Clara Kim 1,  Brian Kleiboeker 4,  Fengrui Zhang 5,  Yongbin Chen 6,  Kristann L Magee 1,  Brian S Learman 7,  Adam Kepecs 5,  Gretchen A Meyer 2 8,  Jun Liu 6,  Steven A Thomas 9,  Irfan J Lodhi 4,  Ormond A MacDougald 7,  Erica L Scheller 10 11 12
Affiliations

Affiliations

  • 1 Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA.
  • 2 Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.
  • 3 Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO, USA.
  • 4 Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA.
  • 5 Department of Neuroscience and Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.
  • 6 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
  • 7 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • 8 Program in Physical Therapy and Departments of Neurology and Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
  • 9 Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
  • 10 Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA. [email protected].
  • 11 Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA. [email protected].
  • 12 Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO, USA. [email protected].
  • # Contributed equally.
PMID: 41507664 DOI: 10.1038/s42255-025-01424-5
Abstract

Several adipose depots, including constitutive bone marrow adipose tissue, resist conventional lipolytic cues. However, under starvation, wasting or cachexia, the body eventually catabolizes stable adipocytes through unknown mechanisms. Here we developed a mouse model of brain-evoked depletion of all fat, including stable constitutive bone marrow adipose tissue, independent of food intake, to study this phenomenon. Genetic, surgical and chemical approaches demonstrated that catabolism of stable adipocytes required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system and catecholamines. Instead, concurrent hypoglycaemia and hypoinsulinaemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors including G0s2. This was also sufficient to delipidate classical adipose depots and was recapitulated in tumour-associated cachexic mice. Overall, this defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent catecholamine-independent neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.

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