Paraventricular hypothalamic RUVBL2 neurons suppress appetite by enhancing excitatory synaptic transmission in distinct neurocircuits.

The paraventricular hypothalamus (PVH) is crucial for food intake control, yet the presynaptic mechanisms underlying PVH neurons remain unclear. Here, we show that RUVBL2 in the PVH is significantly reduced during energy deficit, and knockout (KO) of PVH RUVBL2 results in hyperphagic obesity in mice. RUVBL2-expressing neurons in the PVH (PVHRUVBL2) exert the anorexigenic effect by projecting to the arcuate hypothalamus, the dorsomedial hypothalamus, and the parabrachial complex. We further demonstrate that PVHRUVBL2 neurons form the synaptic connections with POMC and AgRP neurons in the ARC. PVH RUVBL2 KO impairs the excitatory synaptic transmission by reducing presynaptic boutons and synaptic vesicles near active zone. Finally, RUVBL2 overexpression in the PVH suppresses food intake and protects against diet induced obesity. Together, this study demonstrates an essential role for PVH RUVBL2 in food intake control, and suggests that modulation of synaptic plasticity could be an effective way to curb appetite and obesity.

Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits.

OBJECTIVE: Intestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues. METHODS: We genetically induced neonatal IGN by overexpressing G6pc1 the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal G6pc1 on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal G6pc1 were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months. RESULTS: Induction of intestinal G6pc1 at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal G6pc1 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism. CONCLUSION: These findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood.

Negative feedback control of hypothalamic feeding circuits by the taste of food.

The rewarding taste of food is critical for motivating animals to eat, but whether taste has a parallel function in promoting meal termination is not well understood. Here, we show that hunger-promoting agouti-related peptide (AgRP) neurons are rapidly inhibited during each bout of ingestion by a signal linked to the taste of food. Blocking these transient dips in activity via closed-loop optogenetic stimulation increases food intake by selectively delaying the onset of satiety. We show that upstream leptin-receptor-expressing neurons in the dorsomedial hypothalamus (DMHLepR) are tuned to respond to sweet or fatty tastes and exhibit time-locked activation during feeding that is the mirror image of downstream AgRP cells. These findings reveal an unexpected role for taste in the negative feedback control of ingestion. They also reveal a mechanism by which AgRP neurons, which are the primary cells that drive hunger, are able to influence the moment-by-moment dynamics of food consumption.

Dietary fat content and absorption shape standard diet devaluation through hunger circuits.

OBJECTIVE: Exposure to 60% high fat diet (HFD) leads to a robust consummatory preference over well-balanced chow standard diet (SD) when mice are presented with a choice. This passive HFD-induced SD devaluation following HFD challenge and withdrawal is highlighted by the significant reduction in SD food intake even in states of caloric deprivation. The elements of HFD that lead to this SD depreciation remains unclear. Possibly important factors include the amount and type of fat contained in a diet as well as past eating experiences dependent on sensory properties including taste and post ingestive feedback. We aimed to explore the role of these components to HFD-induced SD devaluation. METHODS: Wildtype mice were longitudinally presented discrete HFDs in conjunction with SD and feeding and metabolic parameters were analyzed. A separate cohort of animals were assessed for acute HFD preference in 3 conditions: 1) ad libitum fed (sated), 2) overnight fasted (physiologically hungry), and 3) ad libitum fed (artificially hungry), elicited through chemogenetic Agouti-related peptide (AgRP) neuron activation. Population dynamics of AgRP neurons were recorded to distinct inaccessible and accessible diets both before and after consummatory experience. Transient receptor potential channel type M5 (TRPM5) knockout mice were used to investigate the role of fat taste perception and preference to HFD-induced SD devaluation. The clinically approved lipase inhibitor orlistat was used to test the contribution of fat absorption to HFD-induced SD devaluation. RESULTS: HFD-induced SD devaluation is dependent on fat content, composition, and preference. This effect scaled both in strength and latency with higher percentages of animal fat. 60% HFD was preferred and almost exclusively consumed in preference to other diets across hours and days, but this was not as evident upon initial introduction over seconds and minutes, suggesting ingestive experience is critical. Optical fiber photometry recordings of AgRP activity supported this notion as neuronal suppression by the different diets was contingent on prior intake. While taste transduced via TRPM5 influenced HFD-evoked weight gain, it failed to impact either HFD preference or HFD-induced SD devaluation. Perturbation of post ingestive feedback through orlistat-mediated diminishment of fat absorption prevented HFD-evoked weight gain and abolished HFD-induced SD devaluation. CONCLUSIONS: Post ingestive feedback via fat digestion is vital for expression of HFD-induced SD devaluation.

Acute elevated dietary fat alone is not sufficient to decrease AgRP projections in the paraventricular nucleus of the hypothalamus in mice.

Within the brain, the connections between neurons are constantly changing in response to environmental stimuli. A prime environmental regulator of neuronal activity is diet, and previous work has highlighted changes in hypothalamic connections in response to diets high in dietary fat and elevated sucrose. We sought to determine if the change in hypothalamic neuronal connections was driven primarily by an elevation in dietary fat alone. Analysis was performed in both male and female animals. We measured Agouti-related peptide (AgRP) neuropeptide and Synaptophysin markers in the paraventricular nucleus of the hypothalamus (PVH) in response to an acute 48 h high fat diet challenge. Using two image analysis methods described in previous studies, an effect of a high fat diet on AgRP neuronal projections in the PVH of male or female mice was not identified. These results suggest that it may not be dietary fat alone that is responsible for the previously published alterations in hypothalamic connections. Future work should focus on deciphering the role of individual macronutrients on neuroanatomical and functional changes.

Changes in gene expression due to aging in the hypothalamus of mice.

Aging generally affects food consumption and energy metabolism. Since the feeding center is located in the hypothalamus, it is a major target for understanding the mechanism of age-related changes in eating behavior and metabolism. To obtain insight into the age-related changes in gene expression in the hypothalamus, we investigated genes whose expression changes with age in the hypothalamus. A DNA microanalysis was performed using hypothalamus samples obtained from young (aged 24 weeks) and old male mice (aged 138 weeks). Gene Ontology (GO) analysis was performed using the identified differentially expressed genes. We observed that the expression of 377 probe sets was significantly altered with aging (177 were upregulated and 200 were downregulated in old mice). As a result of the GO analysis of these probe sets, 16 GO terms, including the neuropeptide signaling pathway, were obtained. Intriguingly, although the food intake in old mice was lower than that in young mice, we found that several neuropeptide genes, such as agouti-related neuropeptide ( Agrp ), neuropeptide Y ( Npy ), and pro-melanin-concentrating hormone ( Pmch ), all of which promote food intake, were upregulated in old mice. In conclusion, this suggests that the gene expression pattern in the hypothalamus is regulated to promote food intake.

Effects of KGM and Degradation Products on Appetite Regulation and Energy Expenditure in High-Fat-Diet Mice via the Adipocyte-Hypothalamus Axis.

Konjac glucomannan (KGM), high-viscosity dietary fiber, is utilized in weight management. Previous investigations on the appetite-suppressing effects of KGM have centered on intestinal responses to nutrients and gastric emptying rates, with less focus on downstream hypothalamic neurons of satiety hormones. In our studies, the molecular mechanisms through which KGM and its degradation products influence energy homeostasis via the adipocyte-hypothalamic axis have been examined. It was found that high-viscosity KGM more effectively stimulates enteroendocrine cells to release glucagon-like peptide-1 (GLP-1) and reduces ghrelin production, thereby activating hypothalamic neurons and moderating short-term satiety. Conversely, low-viscosity DKGM has been shown to exhibit stronger anti-inflammatory properties in the hypothalamus, enhancing hormone sensitivity and lowering the satiety threshold. Notably, both KGM and DKGM significantly reduced leptin signaling and fatty acid signaling in adipose tissue and activated brown adipose tissue thermogenesis to suppress pro-opiomelanocortin (POMC) expression and activate agouti-related protein (AgRP) expression, thereby reducing food intake and increasing energy expenditure. Additionally, high-viscosity KGM has been found to activate the adipocyte-hypothalamus axis more effectively than DKGM, thereby promoting greater daily energy expenditure. These findings provide novel insights into the adipocyte-hypothalamic axis for KGM to suppress appetite and reduce weight.

Agouti-Induced Anxiety-Like Behavior Is Mediated by Central Serotonergic Pathways in Zebrafish.

Overexpression of the agouti-signaling protein (asip1), an endogenous melanocortin antagonist, under the control of a constitutive promoter in zebrafish [Tg(Xla.Eef1a1:Cau.Asip1]iim4] (asip1-Tg) increases food intake by reducing sensitivity of the central satiety systems and abolish circadian activity rhythms. The phenotype also shows increased linear growth and body weight, yet no enhanced aggressiveness in dyadic fights is observed. In fact, asip1-Tg animals choose to flee to safer areas rather than face a potential threat, thus suggesting a potential anxiety-like behavior (ALB). Standard behavioral tests, i.e., the open field test (OFT), the novel object test (NOT), and the novel tank dive test (NTDT), were used to investigate thigmotaxis and ALB in male and female zebrafish. Results showed that the asip1-Tg strain exhibited severe ALB in every test, mainly characterized by pronounced freezing behavior and increased linear and angular swimming velocities. asip1-Tg animals exhibited low central serotonin (5-HT) and dopamine (DA) levels and high turnover rates, thus suggesting that central monoaminergic pathways might mediate melanocortin antagonist-induced ALB. Accordingly, the treatment of asip1-Tg animals with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), reversed the ALB phenotype in NTDT as well as 5-HT turnover. Genomic and anatomical data further supported neuronal interaction between melanocortinergic and serotonergic systems. These results suggest that inhibition of the melanocortin system by ubiquitous overexpression of endogenous antagonist has an anxiogenic effect mediated by serotonergic transmission.

Chemogenetic activation of arcuate nucleus NPY and NPY/AgRP neurons increases feeding behaviour in mice.

Neuropeptide Y (NPY) plays a crucial role in controlling energy homeostasis and feeding behaviour. The role of NPY neurons located in the arcuate nucleus of the hypothalamus (Arc) in responding to homeostatic signals has been the focus of much investigation, but most studies have used AgRP promoter-driven models, which do not fully encompass Arc NPY neurons. To directly investigate NPY-expressing versus AgRP-expressing Arc neurons function, we utilised chemogenetic techniques in NPY-Cre and AgRP-Cre animals to activate Arc NPY or AgRP neurons in the presence of food and food-related stimuli. Our findings suggest that chemogenetic activation of the broader population of Arc NPY neurons, including AgRP-positive and AgRP-negative NPY neurons, has equivalent effects on feeding behaviour as activation of Arc AgRP neurons. Our results demonstrate that these Arc NPY neurons respond specifically to caloric signals and do not respond to non-caloric signals, in line with what has been observed in AgRP neurons. Activating Arc NPY neurons significantly increases food consumption and influences macronutrient selection to prefer fat intake.

NPY-mediated synaptic plasticity in the extended amygdala prioritizes feeding during starvation.

Efficient control of feeding behavior requires the coordinated adjustment of complex motivational and affective neurocircuits. Neuropeptides from energy-sensing hypothalamic neurons are potent feeding modulators, but how these endogenous signals shape relevant circuits remains unclear. Here, we examine how the orexigenic neuropeptide Y (NPY) adapts GABAergic inputs to the bed nucleus of the stria terminalis (BNST). We find that fasting increases synaptic connectivity between agouti-related peptide (AgRP)-expressing 'hunger' and BNST neurons, a circuit that promotes feeding. In contrast, GABAergic input from the central amygdala (CeA), an extended amygdala circuit that decreases feeding, is reduced. Activating NPY-expressing AgRP neurons evokes these synaptic adaptations, which are absent in NPY-deficient mice. Moreover, fasting diminishes the ability of CeA projections in the BNST to suppress food intake, and NPY-deficient mice fail to decrease anxiety in order to promote feeding. Thus, AgRP neurons drive input-specific synaptic plasticity, enabling a selective shift in hunger and anxiety signaling during starvation through NPY.

BCAAs acutely drive glucose dysregulation and insulin resistance: role of AgRP neurons.

BACKGROUND: High-protein diets are often enriched with branched-chain amino acids (BCAAs) known to enhance protein synthesis and provide numerous physiological benefits, but recent studies reveal their association with obesity and diabetes. In support of this, protein or BCAA supplementation is shown to disrupt glucose metabolism while restriction improves it. However, it is not clear if these are primary, direct effects of BCAAs or secondary to other physiological changes during chronic manipulation of dietary BCAAs. METHODS: Three-month-old C57Bl/6 mice were acutely treated with either vehicle/BCAAs or BT2, a BCAA-lowering compound, and detailed in vivo metabolic phenotyping, including frequent sampling and pancreatic clamps, were conducted. RESULTS: Using a catheter-guided frequent sampling method in mice, here we show that a single infusion of BCAAs was sufficient to acutely elevate blood glucose and plasma insulin. While pre-treatment with BCAAs did not affect glucose tolerance, a constant infusion of BCAAs during hyperinsulinemic-euglycemic clamps impaired whole-body insulin sensitivity. Similarly, a single injection of BT2 was sufficient to prevent BCAA rise during fasting and markedly improve glucose tolerance in high-fat-fed mice, suggesting that abnormal glycemic control in obesity may be causally linked to high circulating BCAAs. We further show that chemogenetic over-activation of AgRP neurons in the hypothalamus, as present in obesity, significantly impairs glucose tolerance that is completely normalized by acute BCAA reduction. Interestingly, most of these effects were demonstrated only in male, but not in female mice. CONCLUSION: These findings suggest that BCAAs per se can acutely impair glucose homeostasis and insulin sensitivity, thus offering an explanation for how they may disrupt glucose metabolism in the long-term as observed in obesity and diabetes. Our findings also reveal that AgRP neuronal regulation of blood glucose is mediated through BCAAs, further elucidating a novel mechanism by which brain controls glucose homeostasis.

GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are effective antiobesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered GLP-1RAs to patients with obesity and observed a heightened sense of preingestive satiation. Analysis of human and mouse brain samples pinpointed GLP-1 receptor (GLP-1R) neurons in the dorsomedial hypothalamus (DMH) as candidates for encoding preingestive satiation. Optogenetic manipulation of DMHGLP-1R neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMHGLP-1R neurons selectively during eating behavior. We further identified that an intricate interplay between DMHGLP-1R neurons and neuropeptide Y/agouti-related peptide neurons of the arcuate nucleus (ARCNPY/AgRP neurons) occurs to regulate food intake. Our findings reveal a hypothalamic mechanism through which GLP-1RAs control preingestive satiation, offering previously unexplored neural targets for obesity and metabolic diseases.

Hypothalamic AgRP neurons regulate the hyperphagia of lactation.

OBJECTIVE: The lactational period is associated with profound hyperphagia to accommodate the energy demands of nursing. These changes are important for the long-term metabolic health of the mother and children as altered feeding during lactation increases the risk of mothers and offspring developing metabolic disorders later in life. However, the specific behavioral mechanisms and neural circuitry mediating the hyperphagia of lactation are incompletely understood. METHODS: Here, we utilized home cage feeding devices to characterize the dynamics of feeding behavior in lactating mice. A combination of pharmacological and behavioral assays were utilized to determine how lactation alters meal structure, circadian aspects of feeding, hedonic feeding, and sensitivity to hunger and satiety signals in lactating mice. Finally, we utilized chemogenetic, immunohistochemical, and in vivo imaging approaches to characterize the role of hypothalamic agouti-related peptide (AgRP) neurons in lactational-hyperphagia. RESULTS: The lactational period is associated with increased meal size, altered circadian patterns of feeding, reduced sensitivity to gut-brain satiety signals, and enhanced sensitivity to negative energy balance. Hypothalamic AgRP neurons display increased sensitivity to negative energy balance and altered in vivo activity during the lactational state. Further, using in vivo imaging approaches we demonstrate that AgRP neurons are directly activated by lactation. Chemogenetic inhibition of AgRP neurons acutely reduces feeding in lactating mice, demonstrating an important role for these neurons in lactational-hyperphagia. CONCLUSIONS: Together, these results show that lactation collectively alters multiple components of feeding behavior and position AgRP neurons as an important cellular substrate mediating the hyperphagia of lactation.

Fasting-induced miR-7a-5p in AgRP neurons regulates food intake.

OBJECTIVE: The molecular control of feeding after fasting is essential for maintaining energy homeostasis, while overfeeding usually leads to obesity. Identifying non-coding microRNAs (miRNAs) that control food intake could reveal new oligonucleotide-based therapeutic targets for treating obesity and its associated diseases. This study aims to identify a miRNA modulating food intake and its mechanism in neuronal regulation of food intake and energy homeostasis. METHODS: A comprehensive genome-wide miRNA screening in the arcuate nucleus of the hypothalamus (ARC) of fasted mice and ad libitum mice was performed. Through stereotactic virus injections, intracerebroventricular injections, and miRNA sponge technology, miR-7a-5p was inhibited specifically in AgRP neurons and the central nervous system, and metabolic phenotypes were monitored. Quantitative real-time PCR, Western blotting, immunofluorescence, whole-cell patch-clamp recording, and luciferase reporter assay were used to investigate the mechanisms underlying miR-7a-5p's regulation of food intake. RESULTS: We found a significant increase in miR-7a-5p levels after fasting. miR-7a-5p was highly expressed in the ARC, and inhibition of miR-7a-5p specifically in AgRP neurons reduced food intake and body weight gain. miR-7a-5p inhibited S6K1 gene expression by binding to its 3'-UTR. Furthermore, the knockdown of ribosomal S6 kinase 1 (S6K1) in AgRP neurons can partially reverse the effects caused by miR-7a-5p inhibition. Importantly, intracerebroventricular administration of the miR-7a-5p inhibitor could also reduce food intake and body weight gain. CONCLUSION: Our findings suggest that miR-7a-5p responds to energy deficit and regulates food intake by fine-tuning mTOR1/S6K1 signaling in the AgRP neurons, which could be a promising oligonucleotide-based therapeutic target for treating obesity and its associated diseases.

Seipin Deficiency Leads to Energy Dyshomeostasis via Inducing Hypothalamic Neuroinflammation and Aberrant Expression of Neuropeptides.

Seipin is a key regulator of lipid metabolism, the deficiency of which leads to severe lipodystrophy. Hypothalamus is the pivotal center of brain that modulates appetite and energy homeostasis, where Seipin is abundantly expressed. Whether and how Seipin deficiency leads to systemic metabolic disorders via hypothalamus-involved energy metabolism dysregulation remains to be elucidated. In the present study, we demonstrated that Seipin-deficiency induced hypothalamic inflammation, reduction of anorexigenic pro-opiomelanocortin (POMC), and elevation of orexigenic agonist-related peptide (AgRP). Importantly, administration of rosiglitazone, a thiazolidinedione antidiabetic agent, rescued POMC and AgRP expression, suppressed hypothalamic inflammation, and restored energy homeostasis in Seipin knockout mice. Our findings offer crucial insights into the mechanism of Seipin deficiency-associated energy imbalance and indicates that rosiglitazone could serve as potential intervening agent towards metabolic disorders linked to Seipin.

GHSR in a Subset of GABA Neurons Controls Food Deprivation-Induced Hyperphagia in Male Mice.

The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)-producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2-expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)-expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2-expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation-induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice.

AgRP neuron cis-regulatory analysis across hunger states reveals that IRF3 mediates leptin's acute effects.

AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles from male mice during three distinct hunger states of satiety, fasting-induced hunger, and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 18 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Measures of IRF3 activation in vitro and in vivo reveal an increase in IRF3 nuclear occupancy following leptin administration. Finally, gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons. Thus, our findings identify IRF3 as a key mediator of the acute hunger-suppressing effects of leptin in AgRP neurons.

Characterization of a new selective glucocorticoid receptor modulator with anorexigenic activity.

Obesity, a worldwide epidemic, leads to various metabolic disorders threatening human health. In response to stress or fasting, glucocorticoid (GC) levels are elevated to promote food intake. This involves GC-induced expression of the orexigenic neuropeptides in agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) via the GC receptor (GR). Here, we report a selective GR modulator (SGRM) that suppresses GR-induced transcription of genes with non-classical glucocorticoid response elements (GREs) such as Agrp-GRE, but not with classical GREs, and via this way may serve as a novel anti-obesity agent. We have identified a novel SGRM, 2-O-trans-p-coumaroylalphitolic acid (Zj7), a triterpenoid extracted from the Ziziphus jujube plant, that selectively suppresses GR transcriptional activity in Agrp-GRE without affecting classical GREs. Zj7 reduces the expression of orexigenic genes in the ARC and exerts a significant anorexigenic effect with weight loss in both high fat diet-induced obese and genetically obese db/db mouse models. Transcriptome analysis showed that Zj7 represses the expression of a group of orexigenic genes including Agrp and Npy induced by the synthetic GR ligand dexamethasone (Dex) in the hypothalamus. Taken together, Zj7, as a selective GR modulator, showed beneficial metabolic activities, in part by suppressing GR activity in non-classical GREs in orexigenic genes. This study demonstrates that a potential anorexigenic molecule may allow GRE-specific inhibition of GR transcriptional activity, which is a promising approach for the treatment of metabolic disorders.

Ironing out obesity.

Obesity is associated with dysfunctions in hypothalamic neurons that regulate metabolism, including agouti-related protein (AgRP)-expressing neurons. In a recent article, Zhang et al. demonstrated that either diet- or genetically induced obesity promoted iron accumulation specifically in AgRP neurons. Preventing iron overload in AgRP neurons mitigated diet-induced obesity and related comorbidities in male mice.

Metabolic sensing in AgRP regulates sucrose preference and dopamine release in the nucleus accumbens.

Hunger increases the motivation for calorie consumption, often at the expense of low-taste appeal. However, the neural mechanisms integrating calorie-sensing with increased motivation for calorie consumption remain unknown. Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus sense hunger, and the ingestion of caloric solutions promotes dopamine release in the absence of sweet taste perception. Therefore, we hypothesised that metabolic-sensing of hunger by AgRP neurons would be essential to promote dopamine release in the nucleus accumbens in response to caloric, but not non-caloric solutions. Moreover, we examined whether metabolic sensing in AgRP neurons affected taste preference for bitter solutions under conditions of energy need. Here we show that impaired metabolic sensing in AgRP neurons attenuated nucleus accumbens dopamine release in response to sucrose, but not saccharin, consumption. Furthermore, metabolic sensing in AgRP neurons was essential to distinguish nucleus accumbens dopamine response to sucrose consumption when compared with saccharin. Under conditions of hunger, metabolic sensing in AgRP neurons increased the preference for sucrose solutions laced with the bitter tastant, quinine, to ensure calorie consumption, whereas mice with impaired metabolic sensing in AgRP neurons maintained a strong aversion to sucrose/quinine solutions despite ongoing hunger. In conclusion, we demonstrate normal metabolic sensing in AgRP neurons drives the preference for calorie consumption, primarily when needed, by engaging dopamine release in the nucleus accumbens.