Abstract
Adipocyte and hepatic lipid metabolism govern whole-body metabolic homeostasis, whereas a disbalance of de novo lipogenesis (DNL) in fat and liver might lead to obesity, with severe co-morbidities. Nevertheless, some obese people are metabolically healthy, but the “protective” mechanisms are not yet known in detail. Especially, the adipocyte-derived molecular mediators that indicate adipose functionality are poorly understood. We studied transgenic mice (alb-SREBP-1c) with a “healthy” obese phenotype, and obob mice with hyperphagia-induced “sick” obesity to analyze the impact of the tissue-specific DNL on the secreted proteins, i.e., the adipokinome, of the primary adipose cells by label-free proteomics. Compared to the control mice, adipose DNL is reduced in both obese mouse models. In contrast, the hepatic DNL is reduced in obob but elevated in alb-SREBP-1c mice. To investigate the relationship between lipid metabolism and adipokinomes, we formulated the “liver-to-adipose-tissue DNL” ratio. Knowledge-based analyses of these results revealed adipocyte functionality with proteins, which was involved in tissue remodeling or metabolism in the alb-SREBP-1c mice and in the control mice, but mainly in fibrosis in the obob mice. The adipokinome in “healthy” obesity is similar to that in a normal condition, but it differs from that in “sick” obesity, whereas the serum lipid patterns reflect the “liver-to-adipose-tissue DNL” ratio and are associated with the adipokinome signature.
Highlights
We have shown that the hepatic overexpression of the transcription active domain of sterol regulatory element-binding protein (SREBP)-1c increases hepatic de novo lipogenesis (DNL), without severe insulin resistance, resulting in a fatty liver and a massively increased adipose tissue mass in mouse models [7,8]
As our analyses revealed a marked difference in the abundance of proteins known to be regulated by or related to fatty acid metabolism or fibrosis (Figure 6), we generated virtual pathways for all proteins related to these
We provide evidence that (i) the “liver-to-adipose-tissue DNL” ratio shows genotype-specific differences; (ii) this DNL-ratio can be monitored in the serum lipid pattern; and (iii) the pattern of the secreted proteins of adipocyte cells are different, indicated as a shift from secreted proteins, mainly involving tissue remodeling in lean and “healthy” obese mice, to metabolic active adipokines and fibrosis in morbid obese mice, corresponding to the health status of the adipose tissue
Summary
Obesity is prone to severe co-morbidities, including diabetes, cardiovascular disease, and lipotoxicity due to ectopic lipid accumulation. Some obese individuals do not suffer from obesity-associated syndromes, which is the so-called phenomenon of “fit and fat”. This was due to a healthy metabolism and insulin-sensitive adipose tissue, which might increase the likelihood of the incidence of a fatty liver. “sick fat” people show an elevated lipid load, inflammation, hyperplasia, insufficient vascularization, and fibrosis of adipose tissue [1,2,3]. The “point of no return” from healthy obese people, with functional adipose tissue, to unhealthy obesity, prone to comorbidities, still remains unknown
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