Integrative neurocircuits that control metabolism and food intake

Systemic metabolism has to be constantly adjusted to the variance of food intake and even be prepared for anticipated changes in nutrient availability. Therefore, the brain integrates multiple homeostatic signals with numerous cues that predict future deviations in energy supply. Recently, our understanding of the neural pathways underlying these regulatory principles—as well as their convergence in the hypothalamus as the key coordinator of food intake, energy expenditure, and glucose metabolism—have been revealed. These advances have changed our view of brain-dependent control of metabolic physiology. In this Review, we discuss new concepts about how alterations in these pathways contribute to the development of prevalent metabolic diseases such as obesity and type 2 diabetes mellitus and how this emerging knowledge may provide new targets for their treatment. Description Editor’s summary The maintenance of body weight is regulated through a complex network of neuronal signaling, hormones, and gut-brain interactions that allow adaptation to food intake and energy expenditure. Defining the nature of the underlying neurocircuitry and how feedback regulation is achieved are important in understanding the development of obesity and its attendant pathologies, such as type 2 diabetes mellitus and cardiovascular diseases. In a Review, Brüning and Fenselau discuss our developing understanding of the neural pathways that underpin food intake, energy expenditure, and systemic metabolism and discuss how this knowledge provides new therapeutic targets to treat obesity. —Gemma Alderton A review discusses recent advances in defining the principles of brain-dependent control of metabolism and their implications for obesity treatment. BACKGROUND There is an ever-increasing population of overweight and obese individuals who exhibit the predisposition for a plethora of obesity-associated disorders, such as type 2 diabetes mellitus, cardiovascular diseases, certain types of cancers, as well as neurodegenerative disorders. Because both energy homeostasis and peripheral metabolism are coordinated through the brain, defining the basic neurobiological mechanisms of metabolic regulation and defining how alterations in these pathways promote obesity development and the onset of obesity-associated metabolic disorders are urgently needed to devise therapeutic interventions for these prevalent diseases. The arcuate nucleus (ARC) of the hypothalamus integrates multiple hormonal and neuronal inputs, signaling nutrient availability of the organism. The core of this hypothalamic control system comprises two neuronal populations, which exert almost opposite functions in the regulation of feeding behavior, energy expenditure, and fuel metabolism. Agouti-related peptide (AgRP) neurons are activated in conditions of energy deficit, are inhibited by the fuel communication signals leptin and insulin, and promote foraging and food consumption. Pro-opiomelanocortin (POMC) neurons are activated in states of positive energy balance and the associated hormonal changes and reduce food intake and increase energy expenditure. Intense research over the past 20 years has revealed that alterations in this circuitry are causally linked to obesity development in mouse models and humans. ADVANCES Recent developments of high-throughput single-cell and single-nucleus RNA-sequencing methods have enabled the definition of cellular subpopulations at unprecedented molecular resolution. Applying these technologies has recently led to the identification of numerous additional food intake and metabolism regulatory neuronal and non-neuronal cell populations in the hypothalamus. In parallel, functional molecular systems approaches have allowed the delineation not only of the functional role of these newly identified cell types in metabolism control but also definition of the neuronal network organization as well as assessment of their activity in freely behaving animals. These experiments revealed that metabolism regulatory neurons are modulated across different timescales, including upon sensory perception of food cues, postingestive signals that originate from the gastrointestinal tract, and more long-term hormonal mediators. The integration of these signals serves to fine-tune metabolic adaptation and associated behaviors in an allostatic manner. These studies have largely advanced our knowledge of the fundamental principles of central nervous system–dependent control of metabolism. They also allowed the definition of new strategies to combat metabolic diseases. These recent advances are highlighted in the Review. OUTLOOK Further expanding on these developments will allow a more holistic insight into the conserved metabolism regulatory cell types and neurocircuits not only in rodent models but also in humans. This new knowledge will aid the definition of how their deregulation is linked to the development of metabolic disturbances. Moreover, such studies will help clarify the mode of action of promising new anti-obesity therapeutics. These include glucagon-like peptide-1 (GLP-1) receptor agonists as well as newly developed polyagonists for different receptors of gut-derived peptides, for which clinical studies have provided evidence for promising efficacy in body weight reduction and metabolic improvement. Furthermore, deeper insights into the molecular signature of metabolism-regulatory cell types and into the synaptic mechanisms underlying their network interaction carry the potential to nurture the development of alternative therapeutic strategies for metabolic diseases. Hypothalamic integration of food-related signals in metabolic control. Key hunger- and satiety-promoting neuronal cell types in the hypothalamus integrate nutrient-related signals across different timescales: (i) upon sensory perception of food, (ii) post-ingestive gut-derived signals, and (iii) hormonal signals that communicate the energy state of the organism. In addition to feeding, these neurocircuits also adapt multiple behaviors and other physiological parameters in peripheral tissues in accordance to the energy state of the organism. CREDIT: (MOUSE IMAGE) N. BURGESS/SCIENCE