PMID- 38193882
OWN - NLM
STAT- Publisher
LR  - 20240109
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
DP  - 2024 Jan 8
TI  - OxPhos in adipose tissue macrophages regulated by BTK enhances their M2-like 
      phenotype and confers a systemic immunometabolic benefit in obesity.
LID - db220275 [pii]
LID - 10.2337/db22-0275 [doi]
AB  - Bruton's tyrosine kinase (BTK) is a non-receptor bound kinase involved in 
      pro-inflammatory signalling in activated macrophages, however, its role within 
      adipose tissue macrophages remains unclear. We have demonstrated that BTK 
      signalling regulates macrophage M2-like polarisation state by up-regulating 
      subunits of mitochondrially encoded electron transport chain Complex I (ND4 and 
      NDL4) and Complex IV (mt-CO1, mt-CO2 and mt-CO3) resulting in an enhanced rate of 
      oxidative phosphorylation (OxPhos) in an NF-kappaB independent manner. Critically, 
      BTK expression is elevated in adipose tissue macrophages from obese individuals 
      with diabetes, while key mitochondrial genes (mtC01, mtC02 and mtC03) are 
      decreased in inflammatory myeloid cells from obese individuals. Inhibition of BTK 
      signalling either globally (Xid mice) or in myeloid cells (LysMCreBTK), or 
      therapeutically (Acalabrutinib) protects HFD-fed mice from developing glycaemic 
      dysregulation by improving signalling through the IRS1/Akt/GSK3beta pathway. The 
      beneficial effects of acalabrutinib treatment are lost in macrophage ablated 
      mice. Inhibition of BTK signalling in myeloid cells but not B-cells, induced a 
      phenotypic switch in adipose tissue macrophages from a pro-inflammatory M1-state 
      to a pro-resolution M2-like phenotype, by shifting macrophage metabolism towards 
      OxPhos. This reduces both local and systemic inflammation and protected mice from 
      the immunometabolic consequences of obesity. Therefore, in BTK we have identified 
      a macrophage specific, druggable target that can regulate adipose tissue 
      polarisation and cellular metabolism that can confer systematic benefit in 
      metabolic syndrome.
CI  - (c) 2024 by the American Diabetes Association.
FAU - Purvis, Gareth S D
AU  - Purvis GSD
AD  - Sir William Dunn School of Pathology, University of Oxford, UK.
AD  - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
AD  - Division of Cardiovascular Medicine, British Heart Foundation Centre for Research 
      Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.
FAU - Collino, Massimo
AU  - Collino M
AD  - Dept of Neurosciences "Rita Levi Montalcini" University of Turin, Turin, IT.
FAU - van Dam, Andrea D
AU  - van Dam AD
AD  - Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of 
      Medicine, University of Oxford, Oxford, UK.
FAU - Einaudi, Giacomo
AU  - Einaudi G
AD  - Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy.
FAU - Ng, Yujung
AU  - Ng Y
AD  - Division of Cardiovascular Medicine, British Heart Foundation Centre for Research 
      Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.
AD  - National Institute for Health (NIHR) Oxford Biomedical Research Centre, Oxford 
      University Hospitals NHS Foundation Trust, Oxford, UK.
FAU - Shanmuganathan, Mayooran
AU  - Shanmuganathan M
AD  - Division of Cardiovascular Medicine, British Heart Foundation Centre for Research 
      Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.
AD  - National Institute for Health (NIHR) Oxford Biomedical Research Centre, Oxford 
      University Hospitals NHS Foundation Trust, Oxford, UK.
FAU - Patel, Smita Y
AU  - Patel SY
AD  - Primary Immunodeficiency Unit, Department of Experimental Medicine, Nuffield 
      Department of Medicine, University of Oxford, NIHR Oxford Biomedical Research 
      Centre, Oxford, UK.
FAU - Thiemermann, Christoph
AU  - Thiemermann C
AD  - The William Harvey Research Institute, Queen Mary University of London, London, 
      UK.
FAU - Channon, Keith M
AU  - Channon KM
AD  - Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
AD  - Division of Cardiovascular Medicine, British Heart Foundation Centre for Research 
      Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.
AD  - National Institute for Health (NIHR) Oxford Biomedical Research Centre, Oxford 
      University Hospitals NHS Foundation Trust, Oxford, UK.
FAU - Greaves, David R
AU  - Greaves DR
AD  - Sir William Dunn School of Pathology, University of Oxford, UK.
CN  - Oxford Acute Myocardial Infarction (OxAMI) Study
LA  - eng
PT  - Journal Article
DEP - 20240108
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
SB  - IM
EDAT- 2024/01/09 13:43
MHDA- 2024/01/09 13:43
CRDT- 2024/01/09 10:32
PHST- 2023/11/28 00:00 [received]
PHST- 2023/12/18 00:00 [accepted]
PHST- 2024/01/09 13:43 [medline]
PHST- 2024/01/09 13:43 [pubmed]
PHST- 2024/01/09 10:32 [entrez]
AID - 154058 [pii]
AID - 10.2337/db22-0275 [doi]
PST - aheadofprint
SO  - Diabetes. 2024 Jan 8:db220275. doi: 10.2337/db22-0275.