The “yo-yo” effect: even after losing weight, it can be easily regained. Image from Enrique Calabuig on Flickr.com, under CC BY-SA 2.0.
Individuals with obesity frequently regain lost weight over time, even following long-term intervention or surgery. However, due to the challenges of working with human fat tissue at a single-cell level, the cellular mechanisms underlying this so-called “yo-yo effect” have long remained a black box.1
Recent work published by Laura Hinte and colleagues identified epigenetic marks in mouse adipocytes, the body’s fat storage cells, which may confer them with a “cellular memory” of obesity. Their findings may help unravel the difficulty behind shifting weight.
The researchers exposed mice to a high-fat diet, induced weight loss by switching them to a standard feed, then isolated their fat tissue.
Using single-nucleus RNA-sequencing (snRNA-seq) – a technique which captures a snapshot of all messenger RNA in individual cell nuclei – the team aimed to identify changes to gene expression patterns after weight loss.
Old habits die hard
In obese mice, genes regulating normal adipocyte metabolism were downregulated. These genes remained downregulated in adipocytes following weight loss, indicating that dietary intervention failed to overturn a loss of fat cell function.
Moreover, this effect was exaggerated in mice receiving a high-fat diet for 25 weeks compared to 12 weeks, suggesting that the longer the exposure to a poor diet, the stronger the cellular memory, and the less adaptable adipocytes become to dietary changes.
Importantly, this finding was mirrored in human tissue: analyses of adipocytes from patients who underwent weight loss surgery unveiled similar lingering gene expression patterns to those from obese participants.
A laboratory mouse. From Rama on Wikimedia Commons, under CC BY-SA 2.0 FR.
So what’s behind this?
The authors hypothesised that epigenetic signatures may underlie these effects. To test this, the team generated epigenetic profiles of mouse adipocytes, exploiting a technique called CUT&Tag to generate a genome-wide map of the histone modifications at promoters, which are used to fine-tune gene expression.
Intriguingly, for mice in the weight-loss group, promoters of genes involved in maintaining adipocyte function retained marks associated with silencing (though note only H3K27me3 was measured here), while DNA sequences that regulate inflammation signalling gained activation-associated modifications. This is relevant because chronic inflammation is associated with insulin resistance, leading to increased fat storage, which in turn is linked to obesity and type 2 diabetes.
These epigenetic modifications may prime adipocytes to become “greedier“. Indeed, adipocytes from weight-loss mice demonstrated greater glucose and palmitate (a fatty acid) uptake compared to mice on a standard diet.
A 3D rendering of a brown fat cell or adipocyte, which contains many lipid droplets (yellow). Mitochondria (purple) and the nucleus (pink) are also visible. Image by scientificanimations.com and sourced (+ slightly modified from) Wikimedia Commons, under CC BY-SA 4.0.
“Yeah, and?”
While the features identified by von Meyenn’s team may not provide a causal explanation for the “yo-yo effect”, their research provides exciting insights into the molecular correlates of obesity. As mentioned in the introduction, doing such work, especially at the single-cell level, in fat cells is no mean feat.
One issue with snRNA-seq, however, is that it does not account for all the messenger RNAs in the cytoplasm actively undergoing transcription. There may therefore be even more genes underlying this “cellular memory” than previously estimated!
The activation marks at inflammation signalling genes is intriguing. Future studies could focus on identifying whether weight loss impacts adipocytes’ interactions with nearby resident immune cells in fat tissue, which are vital players in launching inflammatory responses.
A final note – there are many, many behavioural and environmental reasons why shifting weight may be difficult, which is hard to boil down to single epigenetic marks, even in mice, and especially in humans. If people are looking to lose weight, they shouldn’t take this study as a sign that doing so is impossible.
Notes
- Fat cells are heterogeneous, often large (which may mean some are excluded from fluidics systems in the sequencing machines), and contain many lipid droplets which make extracting DNA trickier. ↩︎
Discussion point
I am experimenting with shorter articles. Let me know what you think! 🙂
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