Complement factors C4 and C3 are down regulated in response to short term overfeeding in healthy young men

Abstract

Insulin resistance is associated with high circulating level of complement factor C3. Animal studies suggest that improper complement activation mediates high-fat-diet-induced insulin resistance. Individuals born with low birth weight (LBW) are at increased risk of developing insulin resistance. We hypothesized that high-fat overfeeding (HFO) increase circulating C3 and induce complement activation in a birth weight differential manner. Twenty LBW and 26 normal birth weight (NBW) young men were studied using a randomised crossover design. Insulin resistance was measured after a control-diet and after 5-days HFO by a hyperinsulinemic-euglycemic-clamp. Circulating C4, C3, ficolins, mannose-binding-lectin, complement activation products C3bc, terminal complement complex (TCC) and complement activation capacity were determined using turbidimetry and ELISA. HFO induced peripheral insulin resistance in LBW individuals only, while both groups had the same degree of hepatic insulin resistance after HFO. Viewing all individuals circulating levels of C4, C3, C3bc, TCC and complement activation capacity decreased paradoxically along the development of insulin resistance after HFO (P = 0.0015, P < 0.0001, P = 0.01, P < 0.0001, P = 0.0002, P < 0.0001, P = 0.0006). Birth weight did not influence these results. This might reflect a hitherto unrecognized down-regulatory mechanism of the complement system. More human studies are needed to understand the underlying physiology and the potential consequences of these findings.Affecting more than 170 million people worldwide, diabetes constitutes a major threat to human health across the world 1 , with type 2 diabetes (T2D) accounting for more than 90% of all cases 2 . Individuals born with low birth weight (LBW) represent a distinct group of individuals with increased risk of developing insulin resistance and T2D due to different molecular and metabolic events during foetal life [3][4][5] . We have previously shown that adult LBW individuals have multiple metabolic defects and an unfavourable metabolic response to short term high-fat overfeeding (HFO) as compared to individuals with normal birth weight (NBW) 6,7 . Subclinical inflammation and improper immune activation may mediate or influence the impact of a high-fat diet on the development of insulin resistance 8 . Particularly the production of pro-inflammatory cytokines by dysfunctional adipocytes and infiltration of macrophages in adipose tissue is thought to induce insulin resistance, but also other immune cells may be involved [8][9][10] . Over the last decades, attention has been drawn to a role of the complement system as well. The complement system consists of tree distinct pathways of proteolytic cascades, namely the classical, alternative and lectin pathway. These pathways generate C3 convertases efficiently cleaving C3 into C3a and C3b11 . This leads to the cleavage of C5 into C5a and C5b and the generation of the C5b-9 terminal complement complex (TCC). Both C3a and C5a are anaphylatoxins and mediate a variety of biol...