Laura J McCulloch1, Laura R Bramwell1, Bridget Knight2, Katarina Kos3. 1. Diabetes and Obesity Research Group, Institute of Biological and Clinical Sciences, University of Exeter, EX2 5DW, United Kingdom of Great Britain and Northern Ireland. 2. Exeter NIHR Clinical Research Facility, RILD, Exeter EX2 5DW, United Kingdom of Great Britain and Northern Ireland. 3. Diabetes and Obesity Research Group, Institute of Biological and Clinical Sciences, University of Exeter, EX2 5DW, United Kingdom of Great Britain and Northern Ireland. Electronic address: K.Kos@exeter.ac.uk.
Abstract
AIMS: Obesity is associated with adipose tissue (AT) dysfunction marked by cellular hypertrophy, inflammation, hypoxia and fibrosis. Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase which regulates triglyceride storage. Recently, inhibition of ANGPTL4 has been suggested as potential treatment for type 2 diabetes. Here we evaluate ANGPTL4's role in diabetes and examine ANGPTL4 in relation to markers of AT dysfunction and fatty liver disease. MATERIALS & METHODS: We obtained a unique set of paired samples from subjects undergoing weight loss surgery including subcutaneous AT (SCAT), omental AT (OMAT), liver, thigh muscle biopsies and serum including a post-surgical SCAT biopsy after 9 months. RESULTS: SCAT ANGPTL4 expression and circulating protein levels were higher in people with diabetes and correlated with glucose levels and HOMA-IR but not BMI. At post-surgical follow up, SCAT ANGPTL4 declined in subjects with diabetes to levels of those without diabetes. ANGPTL4 expression correlated with HIF1A and inflammation (MCP-1, IL-6). CONCLUSIONS: We found that SCAT ANGPTL4 was closely linked with the expression of ANGPTL4 in the liver and represented a good proxy for liver steatosis. We suggest the elevation of ANGPTL4 levels in diabetes and the association with inflammation and hypoxia is due to a compensatory mechanism to limit further AT dysfunction. A reduction of ANGPTL4 for the treatment of T2DM as previously suggested is thus unlikely to be of further benefit.
AIMS: Obesity is associated with adipose tissue (AT) dysfunction marked by cellular hypertrophy, inflammation, hypoxia and fibrosis. Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase which regulates triglyceride storage. Recently, inhibition of ANGPTL4 has been suggested as potential treatment for type 2 diabetes. Here we evaluate ANGPTL4's role in diabetes and examine ANGPTL4 in relation to markers of AT dysfunction and fatty liver disease. MATERIALS & METHODS: We obtained a unique set of paired samples from subjects undergoing weight loss surgery including subcutaneous AT (SCAT), omental AT (OMAT), liver, thigh muscle biopsies and serum including a post-surgical SCAT biopsy after 9 months. RESULTS: SCAT ANGPTL4 expression and circulating protein levels were higher in people with diabetes and correlated with glucose levels and HOMA-IR but not BMI. At post-surgical follow up, SCAT ANGPTL4 declined in subjects with diabetes to levels of those without diabetes. ANGPTL4 expression correlated with HIF1A and inflammation (MCP-1, IL-6). CONCLUSIONS: We found that SCAT ANGPTL4 was closely linked with the expression of ANGPTL4 in the liver and represented a good proxy for liver steatosis. We suggest the elevation of ANGPTL4 levels in diabetes and the association with inflammation and hypoxia is due to a compensatory mechanism to limit further AT dysfunction. A reduction of ANGPTL4 for the treatment of T2DM as previously suggested is thus unlikely to be of further benefit.
Authors: Philip M M Ruppert; Charlotte C J R Michielsen; Eric J Hazebroek; Ali Pirayesh; Gunilla Olivecrona; Lydia A Afman; Sander Kersten Journal: Mol Metab Date: 2020-06-03 Impact factor: 7.422
Authors: José Manuel Leiva-Valderrama; Adrián Montes-de-Oca-Garcia; Edgardo Opazo-Diaz; Jesus G Ponce-Gonzalez; Guadalupe Molina-Torres; Daniel Velázquez-Díaz; Alejandro Galán-Mercant Journal: Int J Environ Res Public Health Date: 2021-11-30 Impact factor: 3.390