Brainstem BDNF neurons are downstream of GFRAL/GLP1R signalling.

Growth differentiation factor 15, GDF15, and glucagon-like peptide-1 (GLP-1) analogues act through brainstem neurons that co-localise their receptors, GDNF-family receptor α-like (GFRAL) and GLP1R, to reduce food intake and body weight. However, their use as clinical treatments is partially hampered since both can also induce sickness-like behaviours, including aversion, that are mediated through a well-characterised pathway via the exterolateral parabrachial nucleus. Here, in mice, we describe a separate pathway downstream of GFRAL/GLP1R neurons that involves a distinct population of brain-derived neurotrophic factor (BDNF) cells in the medial nucleus of the tractus solitarius.

Paraventricular oxytocin neurons impact energy intake and expenditure: projections to the bed nucleus of the stria terminalis reduce sucrose consumption.

Background: The part played by oxytocin and oxytocin neurons in the regulation of food intake is controversial. There is much pharmacological data to support a role for oxytocin notably in regulating sugar consumption, however, several recent experiments have questioned the importance of oxytocin neurons themselves.

Methods: Here we use a combination of histological and chemogenetic techniques to investigate the selective activation or inhibition of oxytocin neurons in the hypothalamic paraventricular nucleus (Oxt).

A rare human variant that disrupts GPR10 signalling causes weight gain in mice.

Disruption of brain-expressed G protein-coupled receptor-10 (GPR10) causes obesity in animals. Here, we identify multiple rare variants in GPR10 in people with severe obesity and in normal weight controls. These variants impair ligand binding and G protein-dependent signalling in cells.

The hypothalamic RFamide, QRFP, increases feeding and locomotor activity: The role of Gpr103 and orexin receptors.

Here we show that central administration of pyroglutamylated arginine-phenylamine-amide peptide (QRFP/26RFa) increases both food intake and locomotor activity, without any significant effect on energy expenditure, thermogenesis or reward. Germline knock out of either of the mouse QRFP receptor orthologs, Gpr103a and Gpr103b, did not produce a metabolic phenotype. However, both receptors are required for the effect of centrally administered QRFP to increase feeding and locomotor activity.

Hypothalamic AgRP neurons exert top-down control on systemic TNF-α release during endotoxemia.

Loss of appetite and negative energy balance are common features of endotoxemia in all animals and are thought to have protective roles by reducing nutrient availability to host and pathogen metabolism. Accordingly, fasting and caloric restriction have well-established anti-inflammatory properties. However, in response to reduced nutrient availability at the cellular and organ levels, negative energy balance also recruits distinct energy-sensing brain circuits, but it is not known whether these neuronal systems have a role in its anti-inflammatory effects.

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation.

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood.

Methods: We employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4.

Do oxytocin neurones affect feeding?

There has been a long history of research on the effects of oxytocin on feeding behaviour. The classic-held view is that the neurohormone is anorexigenic at least in rodents, although the data for humans are not so clear cut. Likewise, a physiological role for oxytocin is disputed.

Ventromedial Nucleus of the Hypothalamus Neurons Under the Magnifying Glass.

The ventromedial nucleus of the hypothalamus (VMH) is a complex brain structure that is integral to many neuroendocrine functions, including glucose regulation, thermogenesis, and appetitive, social, and sexual behaviors. As such, it is of little surprise that the nucleus is under intensive investigation to decipher the mechanisms which underlie these diverse roles. Developments in genetic and investigative tools, for example the targeting of steroidogenic factor-1-expressing neurons, have allowed us to take a closer look at the VMH, its connections, and how it affects competing behaviors.

The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling.

The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here, we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse.

Brain control of appetite during sickness.

Given the high-energy requirements to sustain immune responses and healing processes, it is intriguing that lack of appetite (i.e., anorexia) is a cardinal feature of sickness behaviour.

Experimental Models of Impaired Hypoglycaemia-Associated Counter-Regulation.

Impaired awareness of hypoglycaemia (IAH) affects around a quarter of patients with diabetes who receive insulin treatment. This condition is characterised by a progressive reduction in symptomatic and behavioural responses to hypoglycaemia, increasing risk of deeper drops in blood glucose, unconsciousness, and collapse. Thus, patients with IAH experience severe hypoglycaemic episodes more frequently, resulting in significant morbidity and mortality.

Modified Peptide YY Molecule Attenuates the Activity of NPY/AgRP Neurons and Reduces Food Intake in Male Mice.

To study the effects of an analog of the gut-produced hormone peptide YY (PYY3-36), which has increased selectivity for the Y2 receptor; specifically, to record its effects on food intake and on hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neuron activity. NNC0165-1273, a modified form of the peptide hormone PYY3-36 with potent selectivity at Y2 receptor (>5000-fold over Y1, 1250-fold over Y4, and 650-fold over Y5 receptor), was tested in vivo and in vitro in mouse models. NNC0165-1273 has fivefold lower relative affinity for Y2 compared with PYY3-36, but >250-, 192-, and 400-fold higher selectivity, respectively, for the Y1, Y4, and Y5 receptors.

PACAP Neurons in the Ventromedial Hypothalamic Nucleus Are Glucose Inhibited and Their Selective Activation Induces Hyperglycaemia.

Glucose-sensing neurons are located in several parts of the brain, but are concentrated in the ventromedial nucleus of the hypothalamus (VMH). The importance of these VMH neurons in glucose homeostasis is well-established, however, little is known about their individual identity. In the present study, we identified a distinct glucose-sensing population in the VMH and explored its place in the glucose-regulatory network.

Central administration of ghrelin induces conditioned avoidance in rodents.

Feelings of hunger carry a negative-valence (emotion) signal that appears to be conveyed through agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus. The circulating hunger hormone, ghrelin, activates these neurons although it remains unclear whether it also carries a negative-valence signal. Given that ghrelin also activates pathways in the midbrain that are important for reward, it remains possible that ghrelin could act as a positive reinforcer and hence, carry a positive-valence signal.

Sequential Exposure to Obesogenic Factors in Females Rats: From Physiological Changes to Lipid Metabolism in Liver and Mesenteric Adipose Tissue.

During their lifetime, females are subjected to different nutritional and hormonal factors that could increase the risk of obesity and associated comorbidities. From early postnatal periods until the postmenopausal phase, exposure to over nutrition, high-energy diet and oestrogen deficiency, are considered as significant obesity risk factors in women. In this study, we assessed how key transitional life events and exposure to different nutrition influence energy homeostasis in a rat model.

The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide neurons in the dorsomedial hypothalamus.

Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin's anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the dorsomedial hypothalamic nucleus (DMH) containing the RFamide PrRP, which is activated by leptin.

Central functional response to the novel peptide cannabinoid, hemopressin.

Hemopressin is the first peptide ligand to be described for the CB₁ cannabinoid receptor. Hemopressin acts as an inverse agonist in vivo and can cross the blood-brain barrier to both inhibit appetite and induce antinociception. Despite being highly effective, synthetic CB₁ inverse agonists are limited therapeutically due to unwanted, over dampening of central reward pathways.

Physiological Roles of GPR10 and PrRP Signaling.

Prolactin-releasing peptide (PrRP) was first isolated from bovine hypothalamus, and was found to act as an endogenous ligand at the G-protein-coupled receptor 10 (GPR10 or hGR3). Although originally named as it can affect the secretion of prolactin from anterior pituitary cells, the potential functions for this peptide have been greatly expanded over the past decade. Anatomical, pharmacological, and physiological studies indicate that PrRP, signaling via the GPR10 receptor, may have a wide range of roles in neuroendocrinology; such as in energy homeostasis, stress responses, cardiovascular regulation, and circadian function.

Functional neuroimaging demonstrates that ghrelin inhibits the central nervous system response to ingested lipid.

Objective: Gut-derived humoural factors activate central nervous system (CNS) mechanisms controlling energy intake and expenditure, and autonomic outflow. Ghrelin is secreted from the stomach and stimulates food intake and gastric emptying, but the relevant mechanisms are poorly understood. Nutrient-activated CNS systems can be studied in humans by physiological/pharmacological MRI (phMRI).

A role for the melatonin-related receptor GPR50 in leptin signaling, adaptive thermogenesis, and torpor.

The ability of mammals to maintain a constant body temperature has proven to be a profound evolutionary advantage, allowing members of this class to thrive in most environments on earth. Intriguingly, some mammals employ bouts of deep hypothermia (torpor) to cope with reduced food supply and harsh climates [1, 2]. During torpor, physiological processes such as respiration, cardiac function, and metabolic rate are severely depressed, yet the neural mechanisms that regulate torpor remain unclear [3].

Set points, settling points and some alternative models: theoretical options to understand how genes and environments combine to regulate body adiposity.

The close correspondence between energy intake and expenditure over prolonged time periods, coupled with an apparent protection of the level of body adiposity in the face of perturbations of energy balance, has led to the idea that body fatness is regulated via mechanisms that control intake and energy expenditure. Two models have dominated the discussion of how this regulation might take place. The set point model is rooted in physiology, genetics and molecular biology, and suggests that there is an active feedback mechanism linking adipose tissue (stored energy) to intake and expenditure via a set point, presumably encoded in the brain.

The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice.

Hemopressin is a short, nine amino acid peptide (H-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His-OH) isolated from rat brain that behaves as an inverse agonist at the cannabinoid receptor CB(1), and is shown here to inhibit agonist-induced receptor internalization in a heterologous cell model. Since this peptide occurs naturally in the rodent brain, we determined its effect on appetite, an established central target of cannabinoid signaling. Hemopressin dose-dependently decreases night-time food intake in normal male rats and mice, as well as in obese ob/ob male mice, when administered centrally or systemically, without causing any obvious adverse side effects.

Hypermetabolism in a triple-transgenic mouse model of Alzheimer's disease.

A common feature of Alzheimer's disease (AD) is weight loss, even though there is often an increase in food intake in AD patients. The reasons for this weight loss are unknown, but may be due to increased energy expenditure (metabolic rate) or a reduction in energy intake. This was investigated in the present study, using a triple-transgenic (3xTgAD) mouse model of AD.

Functional magnetic resonance imaging and c-Fos mapping in rats following a glucoprivic dose of 2-deoxy-D-glucose.

The glucose analogue, 2-deoxy-D-glucose (2-DG) is an inhibitor of glycolysis and, when administered systemically or centrally, induces glucoprivation leading to counter-regulatory responses, including increased feeding behaviour. Investigations into how the brain responds to glucoprivation could have important therapeutic potential, as disruptions or defects in the defence of the brain's 'glucostatic' circuitry may be partly responsible for pathological conditions resulting from diabetes and obesity. To define the 'glucostat' brain circuitry further we have combined blood-oxygen-level-dependent pharmacological-challenge magnetic resonance imaging (phMRI) with whole-brain c-Fos functional activity mapping to characterise brain regions responsive to an orexigenic dose of 2-DG [200 mg/kg; subcutaneous (s.

PACAP neurons in the hypothalamic ventromedial nucleus are targets of central leptin signaling.

The adipose-derived hormone, leptin, was discovered over 10 years ago, but only now are we unmasking its downstream pathways which lead to reduced energy intake (feeding) and increased energy expenditure (thermogenesis). Recent transgenic models have challenged the long-standing supposition that the hypothalamic arcuate nucleus (Arc) is omnipotent in the central response to leptin, and research focus is beginning to shift to examine roles of extra-arcuate sites. Dhillon et al.