Please cite this article in press as: Denis RGP, et al. Central orchestration of peripheral nutrient partitioning and substrate utilization: Implications for the metabolic syndrome. Diabetes Metab (2014), http://dx.doi.org/10.1016/j.diabet.2013.11.002 ARTICLE IN PRESS +Model DIABET-576; No. of Pages 7 Available online at ScienceDirect www.sciencedirect.com Diabetes & Metabolism xxx (2014) xxx–xxx Review Central orchestration of peripheral nutrient partitioning and substrate utilization: Implications for the metabolic syndrome R.G.P. Denis a,1 , A. Joly-Amado a,1 , C. Cansell a,1 , J. Castel a,b , S. Martinez a,b , A.S. Delbes a,b , S. Luquet a,*,b a Unité « biologie fonctionnelle et adaptative » (BFA), université Paris Diderot-Paris 7, CNRS EAC 4413, 4, rue Marie-Andrée-Lagroua-Weill-Hallé, bâtiment Buffon, case courrier 7126, 75205 Paris cedex 13, France b Centre national de la recherche scientifique-CNRS, EAC 4413, 75205 Paris, France Received 18 October 2013; accepted 11 November 2013 Abstract Energy homoeostasis is maintained through a complex interplay of nutrient intake and energy expenditure. The central nervous system is an essential component of this regulation, as it integrates circulating signals of hunger and satiety to develop adaptive responses at the behavioural and metabolic levels, while the hypothalamus is regarded as a particularly crucial structure in the brain in terms of energy homoeostasis. The arcuate nucleus (ARC) of the hypothalamus contains at least two intermingled neuronal populations: the neurons that produce neuropeptide Y (NPY); and the Agouti-related protein (AgRP) produced by AgRP/NPY neurons situated below the third ventricle in close proximity to proopiomelanocortin (POMC)-producing neurons. POMC neurons exert their catabolic and anorectic actions by releasing -melanocyte-stimulating hormone (-MSH), while AgRP neurons oppose this action by exerting tonic GABAergic inhibition of POMC neurons and releasing the melanocortin receptor inverse agonist AgRP. The release of neurotransmitters and neuropeptides by second-order AgRP neurons appears to take place on a multiple time scale, thereby allowing neuromodulation of preganglionic neuronal activity and subsequent control of nutrient partitioning – in other words, the coordinated regulation of conversion, storage and utilization of carbohydrates vs. lipids. This suggests that the function of AgRP neurons extends beyond the strict regulation of feeding to the regulation of efferent organ activity, such that AgRP neurons may now be viewed as an important bridge between central detection of nutrient availability and peripheral nutrient partitioning, thus providing a mechanistic link between obesity and obesity-related disorders. © 2013 Elsevier Masson SAS. All rights reserved. Keywords: Obesity; Diabetes; Nutrient partitioning; Hypothalamus; Agouti-related peptide 1. Introduction The current abundance of energy-rich foods combined with a shift to more sedentary lifestyles has led to thermodynamic imbalance. As a consequence, excess calorie intake and reduced energy expenditure are now the main causes behind the prevalence of obesity as well as obesity-related diseases such as atherosclerosis, hypertension, dyslipidaemia, coronary diseases and diabetes in both developing and developed countries [1]. This constellation of pathophysiology has been dubbed ‘the metabolic syndrome’ or ‘syndrome X’ and, although genetic factors account for some cases of obesity, it is evident that * Corresponding author. E-mail address: serge.luquet@univ-paris-diderot.fr (S. Luquet). 1 The authors contributed equally to this work. drastic environmental changes in combination with both inher- ited and acquired susceptibly are instrumental in its pandemic development. In particular, a drastic change in eating habits is now emerging as one of the main causes of the prevalence of obesity, and this is also driving the concomitant epidemic of type 2 diabetes (T2D) as both are pathophysiologically intimately associated [2,3]. The World Health Organization (WHO; www.who.int/ mediacentre/factsheets/fs311/en/) has highlighted the fact that obesity worldwide has more than doubled since 1980. In 2008, 1.5 billion adults aged 20 and older were overweight. The French Healthcare System may now also consider obesity an epidemic. A recent report from the French Sénat (Senate) has highlighted the dramatic progression of obesity in France (www.senat.fr/rap/r10-158/r10-1580.html#toc0), leading to the launch in 2011 of an obesity plan (plan obésité) backed by the highest authorities. According to the WHO, the fundamental 1262-3636/$ – see front matter © 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.diabet.2013.11.002