2. Academic Validation
  3. Adipocyte inflammation is the primary driver of hepatic insulin resistance in a human iPSC-based microphysiological system

Adipocyte inflammation is the primary driver of hepatic insulin resistance in a human iPSC-based microphysiological system

  • Nat Commun. 2024 Sep 12;15(1):7991. doi: 10.1038/s41467-024-52258-w.
Lin Qi # 1,  Marko Groeger # 2 3,  Aditi Sharma 3 4 5,  Ishan Goswami 6,  Erzhen Chen 1,  Fenmiao Zhong 1,  Apsara Ram 3 4 5,  Kevin Healy 6 7,  Edward C Hsiao 3 4 5,  Holger Willenbring 8 9 10,  Andreas Stahl 11
Affiliations

Affiliations

  • 1 Department of Nutritional Science and Toxicology, College of Natural Resources, University of California Berkeley, Berkeley, CA, 94720, USA.
  • 2 Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA, 94143, USA.
  • 3 Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
  • 4 Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
  • 5 Institute for Human Genetics, University of California San Francisco, San Francisco, CA, 94143, USA.
  • 6 Department of Bioengineering, College of Engineering, University of California Berkeley, Berkeley, CA, 94720, USA.
  • 7 Department of Materials Science and Engineering, College of Engineering, University of California Berkeley, Berkeley, CA, 94720, USA.
  • 8 Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, CA, 94143, USA. holger.willenbring@ucsf.edu.
  • 9 Eli and Edythe Broad Center for Regeneration Medicine, University of California San Francisco, San Francisco, CA, 94143, USA. holger.willenbring@ucsf.edu.
  • 10 Liver Center, University of California San Francisco, San Francisco, CA, 94143, USA. holger.willenbring@ucsf.edu.
  • 11 Department of Nutritional Science and Toxicology, College of Natural Resources, University of California Berkeley, Berkeley, CA, 94720, USA. astahl@berkeley.edu.
  • # Contributed equally.
PMID: 39266553 DOI: 10.1038/s41467-024-52258-w
Abstract

Interactions between adipose tissue, liver and immune system are at the center of metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. To address the need for an accurate in vitro model, we establish an interconnected microphysiological system (MPS) containing white adipocytes, hepatocytes and proinflammatory macrophages derived from isogenic human induced pluripotent stem cells. Using this MPS, we find that increasing the adipocyte-to-hepatocyte ratio moderately affects hepatocyte function, whereas macrophage-induced adipocyte inflammation causes lipid accumulation in hepatocytes and MPS-wide Insulin resistance, corresponding to initiation of metabolic dysfunction-associated steatotic liver disease. We also use our MPS to identify and characterize pharmacological intervention strategies for hepatic steatosis and systemic Insulin resistance and find that the glucagon-like peptide-1 receptor agonist semaglutide improves hepatocyte function by acting specifically on adipocytes. These results establish our MPS modeling the adipose tissue-liver axis as an alternative to animal models for mechanistic studies or drug discovery in metabolic diseases.

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