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Regulation of energy intake and mechanisms of metabolic adaptation or maladaptation after caloric restriction

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Despite their critical role in susceptibility to metabolic diseases such as obesity and type 2 diabetes, mechanisms regulating energy balance are extremely complex and far from being fully understood. Both central and peripheral feedback circuits are involved and, despite it was traditionally thought that the energy balance of an organism depends on the equality between calorie intake within the system and energy expenditure, the regulation of energy content in biological systems oversteps the classical physical laws of thermodynamics. The fine-tuned mechanism for body weight and energy storage regulation is aimed to preserve survival chances in response to the variations of energy availability, as expressed by the metabolic flexibility of this system adapting subjects to both starvation and overfeeding. However, these mechanisms can lose their flexibility, with consequent maladaptation to both increased energy intake and calorie restriction leading to the development of several metabolic disturbances.

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α-melanocyte-stimulating hormone


agouti-related protein


adenosine monophosphate


adenosine triphosphate


brown adipose tissue


body mass index


body weight


Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy


central nervous system


caloric restriction


cAMP response element-binding protein


DIabetes REmission Clinical Trial


energy expenditure


energy intake


free fatty acids


fibroblast growth factor-21


glucagon-like peptide 1


low calorie diet


melanocortin-4 receptor


neuropeptide Y


peroxisome proliferator-activated receptor gamma coactivator 1-α




peroxisome proliferator-activated receptor-α


randomized controlled trial


resting energy expenditure


very low calorie diet


white adipose tissue


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Correspondence to Roberto Vettor.

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Vettor, R., Di Vincenzo, A., Maffei, P. et al. Regulation of energy intake and mechanisms of metabolic adaptation or maladaptation after caloric restriction. Rev Endocr Metab Disord 21, 399–409 (2020).

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