Deletion of Serum Amyloid A3 Improves High Fat High Sucrose Diet-Induced Adipose Tissue Inflammation and Hyperlipidemia in Female Mice

Abstract

Serum amyloid A (SAA) increases in response to acute inflammatory stimuli and is modestly and chronically elevated in obesity. SAA3, an inducible form of SAA, is highly expressed in adipose tissue in obese mice where it promotes monocyte chemotaxis, providing a mechanism for the macrophage accumulation that occurs with adipose tissue expansion in obesity. Humans do not express functional SAA3 protein, but instead express SAA1 and SAA2 in hepatic as well as extrahepatic tissues, making it difficult to distinguish between liver and adipose tissue-specific SAA effects. SAA3 does not circulate in plasma, but may exert local effects that impact systemic inflammation. We tested the hypothesis that SAA3 contributes to chronic systemic inflammation and adipose tissue macrophage accumulation in obesity using mice deficient for Saa3 (Saa3 −/−). Mice were rendered obese by feeding a pro-inflammatory high fat, high sucrose diet with added cholesterol (HFHSC). Both male and female Saa3 −/− mice gained less weight on the HFHSC diet compared to Saa3+/+ littermate controls, with no differences in body composition or resting metabolism. Female Saa3 −/− mice, but not males, had reduced HFHSC diet-induced adipose tissue inflammation and macrophage content. Both male and female Saa3 −/− mice had reduced liver Saa1 and Saa2 expression in association with reduced plasma SAA. Additionally, female Saa3 −/− mice, but not males, showed improved plasma cholesterol, triglycerides, and lipoprotein profiles, with no changes in glucose metabolism. Taken together, these results suggest that the absence of Saa3 attenuates liver-specific SAA (i.e., SAA1/2) secretion into plasma and blunts weight gain induced by an obesogenic diet. Furthermore, adipose tissue-specific inflammation and macrophage accumulation are attenuated in female Saa3 −/− mice, suggesting a novel sexually dimorphic role for this protein. These results also suggest that Saa3 influences liver-specific SAA1/2 expression, and that SAA3 could play a larger role in the acute phase response than previously thought.

Association of Serum Amyloid A with Kidney Outcomes and All-Cause Mortality in American Indians with Type 2 Diabetes

“…SAA is immunologically active, promoting expression of cytokines such as interleukin-1 beta, interleukin-6, interleukin-8, and tumor necrosis factor (TNF) alpha by fibroblasts [4] and macrophages [5]. SAA knockout mice fed a high-fat, high-sucrose diet displayed decreased expression of TNF and monocyte chemoattractant protein-1 and attenuated macrophage accumulation in visceral fat [29]. SAA is a ligand for many receptors involved in immune functions, including toll-like receptors and the receptor for advanced glycation end products [30, 31], and it can trigger pro-inflammatory cascades through activation of transcription factors such as nuclear factor kappa B, activator protein 1, and interferon regulatory factor 3 [6, 32].…”

Serum amyloid A links endotoxaemia to weight gain and insulin resistance in mice

“…It is important to highlight that although no evidence was found for a role of SAA in the development of obesity and insulin resistance in a transgenic mouse model expressing human SAA1 in the adipose tissue [40], a recent study with Saa-knockout mice for isoform 3 showed an attenuated weight gain and macrophage infiltration into the adipose tissue after an obesogenic diet [41]. It is interesting to note that these effects were exclusive for female knockout mice.…”

Serum amyloid A1: Structure, function and gene polymorphism

“…When fed with high fat and high sucrose diet, the commonly seen weight gain and adipose tissue inflammation were improved. Female Saa3 −/− mice also saw improved plasma cholesterol, triglycerides and lipoproteins profiles than the wild type controls (den Hartigh et al, 2014). Interestingly, hepatic production of Saa1 and Saa2 was reduced in Saa3 −/− mice.…”