O-GlcNAc cycling mediates energy balance by regulating caloric memory

Björn Andersson,Ee Phie Tan,Steven R Mcgreal,Udayan Apte,John A Hanover,Chad Slawson,Olof Lagerlöf

doi:10.1016/j.appet.2021.105320

Abstract

Caloric need has long been thought a major driver of appetite. However, it is unclear whether caloric need regulates appetite in environments offered by many societies today where there is no shortage of food. Here we observed that wildtype mice with free access to food did not match calorie intake to calorie expenditure. While the size of a meal affected subsequent intake, there was no compensation for earlier under- or over-consumption. To test how spontaneous eating is subject to caloric control, we manipulated O-linked β-N-acetylglucosamine (O-GlcNAc), an energy signal inside cells dependent on nutrient access and metabolic hormones. Genetic and pharmacological manipulation in mice increasing or decreasing O-GlcNAcylation regulated daily intake by controlling meal size. Meal size was affected at least in part due to faster eating speed. Without affecting meal frequency, O-GlcNAc disrupted the effect of caloric consumption on future intake. Across days, energy balance was improved upon increased O-GlcNAc levels and impaired upon removal of O-GlcNAcylation. Rather than affecting a perceived need for calories, O-GlcNAc regulates how a meal affects future intake, suggesting that O-GlcNAc mediates a caloric memory and subsequently energy balance.

Highlights

Energy need has long been considered a dominating driver of appetite (Adolph, 1947; Richter, 1927; Saper, Chou, & Elmquist, 2002; Waterson & Horvath, 2015)
No difference was seen between wildtypes and O-GlcNAc modulated mice and the negative values were removed from analyses
Our results indicate that cycling of the posttranslational modification O-GlcNAc regulates appetite by mediating a caloric memory that is critical to maintain energy balance and protect against obesity

Summary

Introduction

Energy need has long been considered a dominating driver of appetite (Adolph, 1947; Richter, 1927; Saper, Chou, & Elmquist, 2002; Waterson & Horvath, 2015). Need-based accounts of food intake often have these circuits calculating need by encoding a target level – or set point – of body fatness against which deviations are measured and corrected L.; Williams, Baskin, & Schwartz, 2006) These different theories can be assumed under a general need-based account that we call here the energy deficit model of food intake. The energy deficit model of food intake predicts that energy balance is protected on a meal-to-meal basis if not perturbed by non-metabolic factors (Chambers, Sandoval, & Seeley, 2013; Heisler & Lam, 2017; Le Magnen & Devos, 1970; Schwartz, 1997; Schwartz, Woods, Porte, Seeley, & Baskin, 2000; Speakman et al, 2011; West, Fey, & Woods, 1984). Hedonic aspects may influence feeding, need-driven regulation of feeding is often argued to work near perfectly as body weight in humans fluctuates on average less than 1 kg per year (Lewis et al, 1997; Ochner, Barrios, Lee, & Pi-Sunyer, 2013; Rose nbaum, Kissileff, Mayer, Hirsch, & Leibel, 2010)

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Results

Conclusion