Focus on neural control of energy homeostasis

A better understanding of how the brain controls whole-body energy use and storage, as well as eating behaviour, will pave the way for improving therapeutics to fight metabolic diseases. This Focus presents a collection of Reviews, Perspectives and research Articles that integrate the most recent evidence on how the brain controls key aspects of whole-body metabolism.

Alcantara and Miranda-Tapia et al. discuss the central mechanisms that dictate eating behaviour, by dissecting the neural circuits involved in food procurement, food consumption, and meal termination.

Nampoothiri et al. discuss the most recent literature that places glial cells as key mediators of energy balance through integration of peripheral signals in discrete brain regions, highlighting the relevance of glia in the pathophysiology of metabolic diseases.

The hindbrain is mostly known to participate in eating behaviour by controlling short-term meal parameters and aversive responses to gut malaise. Cheng et al. review current evidence revealing non-aversive neuronal circuits in the hindbrain that are relevant for initiation and termination of homeostatic feeding, as well as for the long-term control of body weight.

In this Perspective, Pekkurnaz and Wang offer an integrative overview on how mitochondrial homeostasis and diversity in morphology, distribution, composition and function contribute to meeting specific cellular demands, with a special focus on neurons

Busquets-García et al. provide a historical perspective of the discovery of endocannabinoid signalling and summarize the most recent findings on the role of endocannabinoids in the regulation of intracellular metabolism and its implications for whole-body homeostasis.

Perino and Schoonjans summarize the most recent literature on the receptor-mediated role of bile acid signalling in the control of peripheral and central energy homeostasis.

Schwartz et al. review mechanisms through which the central nervous system achieves metabolic homeostasis in the basal and postprandial states, and how dysfunction of this integrated central fuel homeostasis control system can contribute to metabolic disease.

Quarta et al. discuss POMC neuronal heterogeneity and how specific subpopulations of POMC neurons can have diverse effects on appetite, whole-body metabolic physiology and the development of obesity.

Extended exposure to breastfeeding in rodent pups protects them from diet-induced obesity in adulthood by increasing thermogenesis and energy expenditure. This is mediated by liver-derived FGF21 signalling to the lateral hypothalamic area.

Ultraviolet exposure on the skin promotes food intake and body weight gain in males, but not females, by increasing ghrelin expression in skin adipocytes.

Hypothalamic AgRP neurons are shown to control peripheral and central levels of lysophospholipids in association with food deprivation, which leads to cortical excitability, hyperphagia and body weight gain.

Milbank et al. show that specific targeting of AMPKα1 in SF1 neurons of the VMH through systemic injection of small extracellular vesicles causes weight loss via increased brown adipose tissue thermogenesis.

Bile acids are shown to enter the brain and regulate short-term reductions in food intake after a meal by inhibiting neuropeptide release from agouti-related peptide/neuropeptide Y neurons.

Irx3 and Irx5 are effectors of the FTO locus, which is associated with obesity. Son et al. show regulation of hypothalamic neurogenesis by Irx3 and Irx5, uncovering a role for these genes in leptin response and energy homeostasis.

When placed in an activity-based anorexia paradigm, mice with altered AgRP circuit function recapitulate characteristics of anorexia nervosa, including a reduction in food intake, compulsive exercise and death.

Zhu and colleagues show that chronic activation of arcuate nucleus GABA⁺ neurons, agouti-related protein (AgRP) neurons alone or non-AgRP GABA⁺ neurons promotes severe obesity, but only inhibition of all GABA⁺ neurons can reverse the obese phenotype of hyperphagic mice, thus suggesting a redundant role for arcuate GABA⁺ neurons in obesity.

The ventromedial nucleus of the hypothalamus is known to maintain energy homeostasis by controlling locomotor activity and thermogenesis. Here van Veen and Kammel et al. identified heterogeneous neuronal populations with sexually dimorphic gene expression and functions by using single-cell RNA analysis.

Ameroso et al. reveal a role for astrocytic brain-derived neurotrophic factor in the hypothalamus for regulating whole body energy homeostasis by means of TrkB.T1 receptor signaling.

Haddad-Tóvolli et al. show that food craving-like episodes in pregnant mice result from a reorganization of the dopaminergic mesolimbic circuitry, and can have long-lasting negative metabolic and neuropsychological effects on the offspring.

The GDF15–GFRAL axis is key for regulating energy homeostasis and body weight. Membrane-bound matrix metalloproteinase 14 is shown to negatively regulate GFRAL, whereas its downregulation protects against diet-induced obesity through increased GDF15 signaling.

In the Drosophila starved brain, memory formation undergoes adaptive plasticity. Silva et al. show that neurons in the olfactory memory centre of the starved fly are fuelled by glial-derived ketone bodies in order to sustain memory formation.

Tanycytic insulin receptors allow insulin access to the hypothalamic arcuate nucleus and are relevant for driving AgRP neuronal activity in response to feeding.

Redox signal transduction from the mitochondrial matrix to the cytosol is shown to be mediated through interaction between MIC60 and Miro, the disruption of which ameliorates oxidative stress in Drosophila.

Irisin is shown to mediate beneficial effects on cognitive function associated with exercise and to improve cognitive function in mouse models of Alzheimer’s disease, probably through its direct action in the brain.

Duquenne et al. show that tanycyte leptin receptor expression is required for leptin to enter the brain and regulate peripheral lipogenesis and pancreatic β-cell function.

Ludwig et al. map transcription and chromatin accessibility in single cells across the brainstem dorsal vagal complex, thereby identifying neuronal populations, including some that control feeding.

Jin et al. show that astrocytic ALDH2 metabolizes ethanol in the brain, thereby attributing behavioural effects of alcohol to metabolites produced in the brain rather than the liver.

GLP-1 is an incretin hormone and neuromodulator produced by gut enterocytes and CNS neurons. Brierley et al. find that GLP-1 from peripheral and central sources acts independently through distinct gut–brain circuits to suppress eating.

Li et al. describe a new form of ATP sensing pathway that induces mitochondrial anchoring at presynaptic terminals during sustained synaptic activity. This mechanism involves AMPK–PAK energy signalling that recruits mitochondria from axons to presynaptic filamentous actin via myosin VI phosphorylation and interaction with the mitochondrial anchoring protein syntaphilin.

Zuend and colleagues show that an arousal-induced increase in cortical activity is accompanied by a surge in lactate in the extracellular space and a substantial lactate dip in astrocytes, followed by mobilization of lactate from glycogen stores and neuronal lactate increase.

Exerkines are signalling moieties that are released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions.

Melanin-concentrating hormone (MCH) integrates physiological functions and mood states associated with energy and glucose homeostasis. In this Review, Al-Massadi et al. describe how MCH regulates the hedonic component of food intake and discuss its potential as a therapeutic target.

The expression of growth differentiation factor 15 (GDF15) is increased under conditions of cellular stress as well as by metformin and exercise. This Review highlights mechanisms of GDF15 production and secretion, GDF15 signalling, and the relevance of GDF15 in obesity and metabolic diseases.

Bariatric surgery is linked with adverse effects on mental health in some patients. This Review summarizes how gut physiology changes after surgery and considers how alterations in gut-derived hormones, microbiota and bile acids can affect gut–brain signalling, with potential consequences for mood and behaviour.

This Review critically evaluates the studies that support and refute the role of brain insulin in systemic nutrient partitioning. The authors discuss the role of brain insulin in metabolic control and the contribution of brain insulin resistance to metabolic disease and assess the therapeutic potential of enhancing or restoring brain insulin signalling in metabolic disease.

The bioactive peptides galanin, spexin and kisspeptin have a common ancestral origin. This Review summarizes the available evidence on the role of these peptides in the regulation of metabolism, pancreatic β-cell function, energy homeostasis, mood and behaviour.

The authors show that stimulus strength-dependent effects of DA on 5-HT^DRN neurons bidirectionally regulate feeding in mice. DRD1-mediated activation of 5-HT^DRN neurons contributes to activity-based anorexia, and this can be prevented by blocking DRD1.

Tuberal nucleus SST⁺ neurons respond to palatable food. The activity of these SST neurons together with their plastic inputs from the ventral subiculum play critical roles in contextually conditioned feeding.

Biglari et al. reveal subgroups of arcuate nucleus hypothalamic neurons that exhibit distinct molecular signatures and feeding-regulatory functions, thus uncovering new regulatory principles in body weight control.

Eiselt et al. report conditions under which mice confuse thirst for hunger, similar to some human decisions that lead to over-eating. Evaluation of physiological need state requires consuming food or water and depends on the prefrontal cortex.

Mazzone and Liang-Guallpa et al. demonstrate that consuming high-fat foods rapidly and durably tunes parallel brain circuits to drive intake of a high-fat diet while devaluing a nutritionally balanced, standard diet even under states of intense hunger.