Enhanced C/EBPβ function promotes hyperplastic versus hypertrophic fat tissue growth and prevents steatosis in response to high-fat diet feeding
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Abstract
Chronic obesity is correlated with severe metabolic and cardiovascular diseases as well as with an increased risk for developing cancers. Obesity is usually characterized by fat accumulation in enlarged – hypertrophic – adipocytes that are a source of inflammatory mediators, which promote the development and progression of metabolic disorders. Yet, in certain healthy obese individuals, fat is stored in metabolically more favorable hyperplastic fat tissue that contains an increased number of smaller adipocytes that are less inflamed. In a previous study, we demonstrated that loss of the inhibitory protein-isoform C/EBPβ-LIP and the resulting augmented function of the transactivating isoform C/EBPβ-LAP promotes fat metabolism under normal feeding conditions and expands health- and lifespan in mice. Here, we show that in mice on a high-fat diet, LIP-deficiency results in adipocyte hyperplasia associated with reduced inflammation and metabolic improvements. Furthermore, fat storage in subcutaneous depots is significantly enhanced specifically in LIP-deficient male mice. Our data identify C/EBPβ as a regulator of adipocyte fate in response to increased fat intake, which has major implications for metabolic health and aging.
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###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on October 2 2020, follows.
Summary
There is consensus among the reviewers that this study provides an interesting and important advance in understanding the role of CEBP/b LAP in metabolism and response to a high fat diet challenge. The major discoveries reported here are fairly well supported by the data, including that male uORF KO mice show an increase in fat cell number as opposed to fat cell size, less inflammation, and improved glucose tolerance/insulin sensitivity.
Essential Revisions
However, all of the reviewers shared the major concern that it appears that only male mice were studied here, and that this fact - or the rationale for using only male mice - was not clearly articulated within the manuscript. This makes …
###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on October 2 2020, follows.
Summary
There is consensus among the reviewers that this study provides an interesting and important advance in understanding the role of CEBP/b LAP in metabolism and response to a high fat diet challenge. The major discoveries reported here are fairly well supported by the data, including that male uORF KO mice show an increase in fat cell number as opposed to fat cell size, less inflammation, and improved glucose tolerance/insulin sensitivity.
Essential Revisions
However, all of the reviewers shared the major concern that it appears that only male mice were studied here, and that this fact - or the rationale for using only male mice - was not clearly articulated within the manuscript. This makes interpretation quite challenging, especially given that the authors previously published that lifespan extension in the uORF KO mice is much more pronounced in female compared to male mice. There was consensus that this is a substantial weakness to the current manuscript which limits its overall impact. It's possible the authors already have this data, and we would need to see inclusion of data supporting similar outcomes for the key experiments in female mice to recommend publication in eLife. If the outcomes are different in males and females, this is likely quite interesting and would need to be developed further.
The other significant concern was related to the RT-qPCR data, which is indicative but not conclusive support for the authors' conclusions, especially since many of the changes are small in magnitude. It was noted that most of the relevant proteins have ELISAs available, and they all have antibodies which could be used to support the robustness and importance of the small but plausibly important differences observed. IHC against CD68 in the fat depots could be performed and the authors could strengthen their claims about adipose tissue inflammation by measuring the expression levels of inflammatory cytokines in adipose depots.
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