Short-Term Cooling Increases Plasma ANGPTL3 and ANGPTL8 in Young Healthy Lean Men but Not in Middle-Aged Men with Overweight and Prediabetes.

Laura G.M Janssen,Kimberly J Nahon,Vesa M Olkkonen,P.A Nidhina Haridas,Patrick C.N Rensen,Matti Jauhiainen,Mariëtte R Boon

doi:10.3390/jcm8081214

Laura G.M Janssen, Kimberly J Nahon + Show 5 more

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https://doi.org/10.3390/jcm8081214

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Abstract

Angiopoietin-like proteins (ANGPTLs) regulate triglyceride (TG)-rich lipoprotein distribution via inhibiting TG hydrolysis by lipoprotein lipase in metabolic tissues. Brown adipose tissue combusts TG-derived fatty acids to enhance thermogenesis during cold exposure. It has been shown that cold exposure regulates ANGPTL4, but its effects on ANGPTL3 and ANGPTL8 in humans have not been elucidated. We therefore investigated the effect of short-term cooling on plasma ANGPTL3 and ANGPTL8, besides ANGPTL4. Twenty-four young, healthy, lean men and 20 middle-aged men with overweight and prediabetes were subjected to 2 h of mild cooling just above their individual shivering threshold. Before and after short-term cooling, plasma ANGPTL3, ANGPTL4, and ANGPTL8 were determined by ELISA. In young, healthy, lean men, short-term cooling increased plasma ANGPTL3 (+16%, p < 0.05), ANGPTL4 (+15%, p < 0.05), and ANGPTL8 levels (+28%, p < 0.001). In middle-aged men with overweight and prediabetes, short-term cooling only significantly increased plasma ANGPTL4 levels (+15%, p < 0.05), but not ANGPTL3 (230 ± 9 vs. 251 ± 13 ng/mL, p = 0.051) or ANGPTL8 (2.2 ± 0.5 vs. 2.3 ± 0.5 μg/mL, p = 0.46). We show that short-term cooling increases plasma ANGPTL4 levels in men, regardless of age and metabolic status, but only overtly increases ANGPTL3 and ANGPTL8 levels in young, healthy, lean men.

Highlights

Increased plasma triacylglycerol (TG) levels are an independent risk factor for cardiovascular disease [1]
Similar observations were made when taking into account South Asian and white Caucasian ethnicities separately (Table S1)
angiopoietin-like proteins (ANGPTLs) are inhibitors of lipoprotein lipase (LPL) activity and function in modulating TG-rich lipoproteins (TRLs) that traffic between tissues depending on specific situational energy demands

Summary

Introduction

Increased plasma triacylglycerol (TG) levels are an independent risk factor for cardiovascular disease [1]. TG is either derived from dietary lipids or synthesized by the liver and white adipose tissue (WAT) from glucose and carried in the circulation within TG-rich lipoproteins (TRLs). TRLs can be hydrolysed by lipoprotein lipase (LPL) on endothelial cells to provide underlying oxidative tissues with fatty acids (FA) as fuel during increased energy demands (fasting or exercise) or to increase lipid storage in WAT during nutrient excess [2]. As energy needs can rapidly change, the LPL-mediated clearance of TRL-derived TG is under strict regulation of several factors including lipoprotein-associated apolipoproteins (e.g., APOC2 and APOC3) and angiopoietin-like proteins (ANGPTLs) [3]. Loss-of-function mutations in either one of these proteins are associated with a favourable lipid profile including lower TG levels in humans [5,6,7,8]. Deficiency for either one of these proteins in mouse models results in lower plasma TG levels, whereas overexpression leads to hypertriglyceridemia [9,10,11,12,13]

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