Hypothalamic detection of macronutrients via multiple gut-brain pathways.
TL;DR: In this paper, the authors found that AgRP neuron activity in hungry mice is inhibited by site-specific intestinal detection of different macronutrients, such as fat and glucose.
About: This article is published in Cell Metabolism.The article was published on 2021-03-02. It has received 81 citations till now. The article focuses on the topics: Neuron.
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TL;DR: A more accurate description of the EBM where the brain is the primary organ responsible for body weight regulation operating primarily below the authors' conscious awareness via complex endocrine, metabolic, and nervous system signals to control food intake in response to environmental influences as well as the body's energy needs is presented.
85 citations
TL;DR: A recent Perspective article described the "carbohydrate-insulin model (CIM)" of obesity, asserting that it "better reflects knowledge on the biology of weight control" as compared with what was described as the "dominant energy balance model (EBM)" which fails to consider "biological mechanisms that promote weight gain" as discussed by the authors .
81 citations
TL;DR: In this article, the authors chart the history of the melanocortin pathway, explore its pharmacology, genetics and physiology, and tell the story of how a neuropeptidergic circuit managed to find its way to becoming an important druggable obesity target.
Abstract: Background Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in the control of mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variation influencing the population distribution of body-weight. At the end of 2020, the Food & Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency. Scope of review Here, we will chart the history of the melanocortin pathway, explore its pharmacology, genetics and physiology, and tell the story of how a neuropeptidergic circuit managed to find its way to becoming an important druggable obesity target. Conclusions Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind the melanocortin receptors has brought a new drug to the market for obesity. This process provides a template of drug discovery for complex disorders, which in the case of setmelanotide took 25 years to go from a single gene to an approved drug.
76 citations
University of Pennsylvania1, Nanyang Technological University2, Monell Chemical Senses Center3, King's College London4, Salk Institute for Biological Studies5, National University of Singapore6, University of Kansas7, Harvard University8, McLean Hospital9, Beth Israel Deaconess Medical Center10, Brigham and Women's Hospital11
TL;DR: In this article, the authors used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation in the anterior deep cerebellum.
Abstract: The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control1–3. Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically -distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a ‘bedside-to-bench’ approach for the identification of neural circuits that influence behaviour. Activity in anterior deep cerebellar nuclei reduces food consumption in mice without reducing metabolic rate, potentially identifying a therapeutic target for disorders involving excessive eating.
55 citations
TL;DR: In this paper, intersectional genetic manipulations were employed to probe the feeding and glucoregulatory function of distinct sensory neurons, and it was shown that distinct gut-innervating sensory neurons differentially control feeding and glucose neurocircuits and may provide specific targets for metabolic control.
55 citations
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TL;DR: In this paper, the authors showed that post-prandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.
Abstract: Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus(1). The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons(2) in the arcuate nucleus, which is accessible to peripheral hormones(3). Peptide YY3-36 (PYY3-36), a Y2R agonist(4), is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal(5-7). Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons(8). In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.
2,110 citations
TL;DR: Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, it is demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores.
Abstract: Several different neuronal populations are involved in regulating energy homeostasis. Among these, agouti-related protein (AgRP) neurons are thought to promote feeding and weight gain; however, the evidence supporting this view is incomplete. Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, we have demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores. All these effects returned to baseline after stimulation was withdrawn. In contrast, inhibiting AgRP neuronal activity in hungry mice reduced food intake. Together, these findings demonstrate that AgRP neuron activity is both necessary and sufficient for feeding. Of interest, activating AgRP neurons potently increased motivation for feeding and also drove intense food-seeking behavior, demonstrating that AgRP neurons engage brain sites controlling multiple levels of feeding behavior. Due to its ease of use and suitability for both acute and chronic regulation, DREADD technology is ideally suited for investigating the neural circuits hypothesized to regulate energy balance.
1,170 citations
TL;DR: AGRP neuron–mediated feeding was not dependent on suppressing this melanocortin pathway, indicating that AGRP neurons directly engage feeding circuits, and feeding was evoked selectively over drinking without training or prior photostimulus exposure, which suggests that A GRP neurons serve a dedicated role coordinating this complex behavior.
Abstract: Two intermingled hypothalamic neuron populations specified by expression of agouti-related peptide (AGRP) or pro-opiomelanocortin (POMC) positively and negatively influence feeding behavior, respectively, possibly by reciprocally regulating downstream melanocortin receptors. However, the sufficiency of these neurons to control behavior and the relationship of their activity to the magnitude and dynamics of feeding are unknown. To measure this, we used channelrhodopsin-2 for cell type-specific photostimulation. Activation of only 800 AGRP neurons in mice evoked voracious feeding within minutes. The behavioral response increased with photoexcitable neuron number, photostimulation frequency and stimulus duration. Conversely, POMC neuron stimulation reduced food intake and body weight, which required melanocortin receptor signaling. However, AGRP neuron-mediated feeding was not dependent on suppressing this melanocortin pathway, indicating that AGRP neurons directly engage feeding circuits. Furthermore, feeding was evoked selectively over drinking without training or prior photostimulus exposure, which suggests that AGRP neurons serve a dedicated role coordinating this complex behavior.
926 citations
TL;DR: Triglyceride elevations are a highly significant independent risk factor for coronary heart disease (CHD) in women and appear to be important in men with low high-density lipoprotein (HDL) cholesterol (less than 40 ml/dl).
670 citations
TL;DR: Two parallel nigrostriatal dopamine neuron subpopulations differing in biophysical properties, input wiring, output wiring to dorsomedial striatum versus dorsolateral striatum (DLS), and natural activity patterns during free behavior are identified.
582 citations