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Abstract
BackgroundChronic metabolic overload results in lipid accumulation and subsequent inflammation in white adipose tissue (WAT), often accompanied by non-alcoholic fatty liver disease (NAFLD). In response to metabolic overload, the expression of genes involved in lipid metabolism and inflammatory processes is adapted. However, it still remains unknown how these adaptations in gene expression in expanding WAT and liver are orchestrated and whether they are interrelated.Methodology/Principal FindingsApoE*3Leiden mice were fed HFD or chow for different periods up to 12 weeks. Gene expression in WAT and liver over time was evaluated by micro-array analysis. WAT hypertrophy and inflammation were analyzed histologically. Bayesian hierarchical cluster analysis of dynamic WAT gene expression identified groups of genes (‘clusters’) with comparable expression patterns over time. HFD evoked an immediate response of five clusters of ‘lipid metabolism’ genes in WAT, which did not further change thereafter. At a later time point (>6 weeks), inflammatory clusters were induced. Promoter analysis of clustered genes resulted in specific key regulators which may orchestrate the metabolic and inflammatory responses in WAT. Some master regulators played a dual role in control of metabolism and inflammation. When WAT inflammation developed (>6 weeks), genes of lipid metabolism and inflammation were also affected in corresponding livers. These hepatic gene expression changes and the underlying transcriptional responses in particular, were remarkably similar to those detected in WAT.ConclusionIn WAT, metabolic overload induced an immediate, stable response on clusters of lipid metabolism genes and induced inflammatory genes later in time. Both processes may be controlled and interlinked by specific transcriptional regulators. When WAT inflammation began, the hepatic response to HFD resembled that in WAT. In all, WAT and liver respond to metabolic overload by adaptations in expression of gene clusters that control lipid metabolism and inflammatory processes in an orchestrated and interrelated manner.
Highlights
The obesity epidemic has become the most important nutritional problem worldwide
The effect of metabolic overload on white adipose tissue (WAT) and liver was analyzed in a mouse model that responds to HFD feeding with WAT expansion, metabolic stress, inflammation and development of non-alcoholic fatty liver disease (NAFLD)
Using Bayesian hierarchical clustering we showed that the expression of genes of lipid metabolism is rapidly adjusted upon HFD feeding
Summary
The obesity epidemic has become the most important nutritional problem worldwide. The increasing prevalence of obesity has been ascribed to excessive and unhealthy eating and reduced physical activity [1] and carries with it increased risks for type 2 diabetes (T2DM) and non-alcoholic fatty liver disease (NAFLD) [2,3,4]. Several studies in mice have demonstrated that the expression of genes of lipid metabolism and inflammation is adjusted in several organs in response to chronic high-fat diet (HFD) feeding [10,11,12] These studies are often static and focus on a single organ which is analyzed at one particular time point, typically at a later stage in the disease process when histopathological effects of HFD can be detected (e.g. crownlike structures in WAT, inflammatory gut, hepatic steatosis). Conclusion: In WAT, metabolic overload induced an immediate, stable response on clusters of lipid metabolism genes and induced inflammatory genes later in time Both processes may be controlled and interlinked by specific transcriptional regulators. WAT and liver respond to metabolic overload by adaptations in expression of gene clusters that control lipid metabolism and inflammatory processes in an orchestrated and interrelated manner
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