title: GLP-1 analogue-induced weight loss does not improve obesity-induced AT dysfunction.
abstract: Glucagon-like peptide-1 (GLP-1) analogues aid weight loss that improves obesity-associated adipose tissue (AT) dysfunction. GLP-1 treatment may however also directly influence AT that expresses the GLP-1 receptor (GLP-1R). The present study aimed to assess the impact of GLP-1 analogue treatment on subcutaneous AT (SCAT) inflammatory and fibrotic responses, compared with weight loss by calorie reduction (control). Among the 39 participants with Type 2 diabetes recruited, 30 age-matched participants were randomized to 4 months treatment with Liraglutide (n=22) or calorie restriction based on dietetic counselling (n=8). Assessments included clinical characteristics and repeated subcutaneous abdominal AT biopsies. Liraglutide resulted in weight loss in most participants (-3.12±1.72 kg,P=0.007) and significant reduction in visceral AT (VAT). It was more effective in lowering fasting glucose, in comparison with weight loss by dieting. However, tumour necrosis factor-α (TNFA) AT-expression (P=0.0005), macrophage chemoattractant protein-1 (MCP-1) expression (P=0.027) and its serum levels (P=0.048) increased with Liraglutide, suggestive of an inflammatory response unlike in the diet arm in which a trend of lower cluster of differentiation 14 (CD14) expression (P=0.09) was found. Liraglutide treatment also increased expression of factors involved in extracellular matrix (ECM) deposition, transforming growth factor-β (TGFB) and collagen type 1 alpha 1 chain (COL1A1) (TGFB1: before 0.73±0.09 arbitrary units (AU), after 1.00±0.13 AU,P=0.006;COL1A1: 0.84±0.09 AU compared with 1.49±0.26 AU,P=0.026). Liraglutide thus appears to induce an inflammatory response in AT and influences ECM remodelling. Despite its superior effect on glycaemia, Liraglutide does not improve obesity-associated AT dysfunction in subcutaneous tissue. It is yet unclear whether this limits AT storage capacity for lipids. This may be of importance in patients being re-exposed to positive energy balance such as post GLP-1 discontinuation.
authors.affiliation: Diabetes and Obesity Research Group, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, U.K.
authors.forename: Emilie
authors.initials: E
authors.lastname: Pastel
authors.affiliation: Diabetes and Obesity Research Group, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, U.K.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: McCulloch
authors.affiliation: Diabetes and Obesity Research Group, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, U.K.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ward
authors.affiliation: Diabetes and Obesity Research Group, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, U.K.
authors.forename: Shivam
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Diabetes and Vascular Medicine, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, U.K.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Gooding
authors.affiliation: Diabetes and Vascular Medicine, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, U.K.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Shore
authors.affiliation: Diabetes and Obesity Research Group, University of Exeter Medical School, Barrack Road, Exeter EX2 5DW, U.K. k.kos@exeter.ac.uk.
authors.forename: Katarina
authors.initials: K
authors.lastname: Kos
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D005109:Extracellular Matrix / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D000069450:Liraglutide / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D052242:Adiponectin; D007004:Hypoglycemic Agents; D020738:Leptin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1
keywords: Liraglutide; Type 2 diabetes; adipose tissue fibrosis; glucagon-like peptide-1 (GLP-1) analogue; obesity