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Journal ArticleDOI

Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism

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.
About: This article is published in Cell Metabolism.The article was published on 2021-07-06 and is currently open access. It has received 55 citations till now. The article focuses on the topics: Sensory system & Stimulation.
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TL;DR: In this paper, the authors discuss the physiology of Glucagon-like peptide-1 (GLP-1) action in the control of food intake in animals and humans.
Abstract: Background Glucagon-like peptide-1 receptor agonists (GLP1RA) augment glucose-dependent insulin release and reduce glucagon secretion and gastric emptying, enabling their successful development for the treatment of type 2 diabetes (T2D). These agents also inhibit food intake and reduce body weight, fostering investigation of GLP1RA for the treatment of obesity. Scope of review Here I discuss the physiology of Glucagon-like peptide-1 (GLP-1) action in the control of food intake in animals and humans, highlighting the importance of gut vs. brain-derived GLP-1 for the control of feeding and body weight. The widespread distribution and function of multiple GLP-1 receptor (GLP1R) populations in the central and autonomic nervous system are outlined, and the importance of pathways controlling energy expenditure in preclinical studies vs. reduction of food intake in both animals and humans is highlighted. The relative contributions of vagal afferent pathways vs. GLP1R+ populations in the central nervous system for the physiological reduction of food intake and the anorectic response to GLP1RA are compared and reviewed. Key data enabling the development of two GLP1RA for obesity therapy (liraglutide 3 mg daily and semaglutide 2.4 mg once weekly) are discussed. Finally, emerging data potentially supporting the combination of GLP-1 with additional peptide epitopes in unimolecular multi-agonists, as well as in fixed-dose combination therapies, are highlighted. Major conclusions The actions of GLP-1 to reduce food intake and body weight are highly conserved in obese animals and humans, in both adolescents and adults. The well-defined mechanisms of GLP-1 action through a single G protein-coupled receptor, together with the extensive safety database of GLP1RA in people with T2D, provide reassurance surrounding the long-term use of these agents in people with obesity and multiple co-morbidities. GLP1RA may also be effective in conditions associated with obesity, such as cardiovascular disease and non-alcoholic steatohepatitis (NASH). Progressive improvements in the efficacy of GLP1RA suggest that GLP-1-based therapies may soon rival bariatric surgery as viable options for the treatment of obesity and its complications.

53 citations

Journal ArticleDOI
TL;DR: In this paper , the authors discuss the physiology of Glucagon-like peptide-1 (GLP-1) action in the control of food intake in animals and humans.
Abstract: Glucagon-like peptide-1 receptor agonists (GLP1RA) augment glucose-dependent insulin release and reduce glucagon secretion and gastric emptying, enabling their successful development for the treatment of type 2 diabetes (T2D). These agents also inhibit food intake and reduce body weight, fostering investigation of GLP1RA for the treatment of obesity.Here I discuss the physiology of Glucagon-like peptide-1 (GLP-1) action in the control of food intake in animals and humans, highlighting the importance of gut vs. brain-derived GLP-1 for the control of feeding and body weight. The widespread distribution and function of multiple GLP-1 receptor (GLP1R) populations in the central and autonomic nervous system are outlined, and the importance of pathways controlling energy expenditure in preclinical studies vs. reduction of food intake in both animals and humans is highlighted. The relative contributions of vagal afferent pathways vs. GLP1R+ populations in the central nervous system for the physiological reduction of food intake and the anorectic response to GLP1RA are compared and reviewed. Key data enabling the development of two GLP1RA for obesity therapy (liraglutide 3 mg daily and semaglutide 2.4 mg once weekly) are discussed. Finally, emerging data potentially supporting the combination of GLP-1 with additional peptide epitopes in unimolecular multi-agonists, as well as in fixed-dose combination therapies, are highlighted.The actions of GLP-1 to reduce food intake and body weight are highly conserved in obese animals and humans, in both adolescents and adults. The well-defined mechanisms of GLP-1 action through a single G protein-coupled receptor, together with the extensive safety database of GLP1RA in people with T2D, provide reassurance surrounding the long-term use of these agents in people with obesity and multiple co-morbidities. GLP1RA may also be effective in conditions associated with obesity, such as cardiovascular disease and non-alcoholic steatohepatitis (NASH). Progressive improvements in the efficacy of GLP1RA suggest that GLP-1-based therapies may soon rival bariatric surgery as viable options for the treatment of obesity and its complications.

53 citations

Journal ArticleDOI
01 Jan 2022-Neuron
TL;DR: A review of the state of knowledge related to vagal sensory neurons that innervate the respiratory, cardiovascular, and digestive systems can be found in this article , where the authors focus on cell types and their response properties, physiological/behavioral roles, engaged neural circuits and sensory receptors.

45 citations

Journal ArticleDOI
TL;DR: In this paper, the authors summarize novel insights with a particular emphasis on ARC neurocircuitries regulating food intake and glucose homeostasis and sensing factors that inform the brain of the organismal energy status.
Abstract: The central nervous system (CNS) receives information from afferent neurons, circulating hormones and absorbed nutrients and integrates this information to orchestrate the actions of the neuroendocrine and autonomic nervous systems in maintaining systemic metabolic homeostasis. Particularly the arcuate nucleus of the hypothalamus (ARC) is of pivotal importance for primary sensing of adiposity signals, such as leptin and insulin, and circulating nutrients, such as glucose. Importantly, energy state-sensing neurons in the ARC not only regulate feeding but at the same time control multiple physiological functions, such as glucose homeostasis, blood pressure and innate immune responses. These findings have defined them as master regulators, which adapt integrative physiology to the energy state of the organism. The disruption of this fine-tuned control leads to an imbalance between energy intake and expenditure as well as deregulation of peripheral metabolism. Improving our understanding of the cellular, molecular and functional basis of this regulatory principle in the CNS could set the stage for developing novel therapeutic strategies for the treatment of obesity and metabolic syndrome. In this review, we summarize novel insights with a particular emphasis on ARC neurocircuitries regulating food intake and glucose homeostasis and sensing factors that inform the brain of the organismal energy status.

44 citations

Journal ArticleDOI
TL;DR: In this paper , the authors present a comprehensive and balanced assessment of how physiological signals associated with energy homeostasis interact at many brain levels to control eating behaviors, and discuss network models of how key regions in the endbrain (or telencephalon), hypothalamus, hindbrain, medulla, vagus nerve, and spinal cord work together with the gastrointestinal tract to enable the complex motor events that permit animals to eat in diverse situations.
Abstract: During the past 30 yr, investigating the physiology of eating behaviors has generated a truly vast literature. This is fueled in part by a dramatic increase in obesity and its comorbidities that has coincided with an ever increasing sophistication of genetically based manipulations. These techniques have produced results with a remarkable degree of cell specificity, particularly at the cell signaling level, and have played a lead role in advancing the field. However, putting these findings into a brain-wide context that connects physiological signals and neurons to behavior and somatic physiology requires a thorough consideration of neuronal connections: a field that has also seen an extraordinary technological revolution. Our goal is to present a comprehensive and balanced assessment of how physiological signals associated with energy homeostasis interact at many brain levels to control eating behaviors. A major theme is that these signals engage sets of interacting neural networks throughout the brain that are defined by specific neural connections. We begin by discussing some fundamental concepts, including ones that still engender vigorous debate, that provide the necessary frameworks for understanding how the brain controls meal initiation and termination. These include key word definitions, ATP availability as the pivotal regulated variable in energy homeostasis, neuropeptide signaling, homeostatic and hedonic eating, and meal structure. Within this context, we discuss network models of how key regions in the endbrain (or telencephalon), hypothalamus, hindbrain, medulla, vagus nerve, and spinal cord work together with the gastrointestinal tract to enable the complex motor events that permit animals to eat in diverse situations.

38 citations

References
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Journal ArticleDOI
TL;DR: The origins, challenges and solutions of NIH Image and ImageJ software are discussed, and how their history can serve to advise and inform other software projects.
Abstract: For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.

44,587 citations

Journal ArticleDOI
06 Apr 2000-Nature
TL;DR: A model is described that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.
Abstract: New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.

6,178 citations

Journal ArticleDOI
TL;DR: This work developed a method that, based on the Fourier Shift Theorem, computes all possible translations between pairs of 3D images, yielding the best overlap in terms of the cross-correlation measure and subsequently finds the globally optimal configuration of the whole group of3D images.
Abstract: Motivation: Modern anatomical and developmental studies often require high-resolution imaging of large specimens in three dimensions (3D). Confocal microscopy produces high-resolution 3D images, but is limited by a relatively small field of view compared with the size of large biological specimens. Therefore, motorized stages that move the sample are used to create a tiled scan of the whole specimen. The physical coordinates provided by the microscope stage are not precise enough to allow direct reconstruction (Stitching) of the whole image from individual image stacks. Results: To optimally stitch a large collection of 3D confocal images, we developed a method that, based on the Fourier Shift Theorem, computes all possible translations between pairs of 3D images, yielding the best overlap in terms of the cross-correlation measure and subsequently finds the globally optimal configuration of the whole group of 3D images. This method avoids the propagation of errors by consecutive registration steps. Additionally, to compensate the brightness differences between tiles, we apply a smooth, non-linear intensity transition between the overlapping images. Our stitching approach is fast, works on 2D and 3D images, and for small image sets does not require prior knowledge about the tile configuration. Availability: The implementation of this method is available as an ImageJ plugin distributed as a part of the Fiji project (FijiisjustImageJ: http://pacific.mpi-cbg.de/). Contact: tomancak@mpi-cbg.de

1,989 citations

Journal ArticleDOI
22 Sep 2011-Neuron
TL;DR: Using genetic engineering in mice, approximately 20 Cre and inducible CreER knockin driver lines that reliably target major classes and lineages of GABAergic neurons are generated, thereby enabling a systematic and comprehensive analysis from cell fate specification, migration, and connectivity, to their functions in network dynamics and behavior.

1,655 citations

Journal ArticleDOI
TL;DR: The results suggest that itching during inflammatory skin diseases such as atopic dermatitis is linked to a distinct itch-generating type, and demonstrate single-cell RNA-seq as an effective strategy for dissecting sensory responsive cells into distinct neuronal types.
Abstract: The primary sensory system requires the integrated function of multiple cell types, although its full complexity remains unclear. We used comprehensive transcriptome analysis of 622 single mouse neurons to classify them in an unbiased manner, independent of any a priori knowledge of sensory subtypes. Our results reveal eleven types: three distinct low-threshold mechanoreceptive neurons, two proprioceptive, and six principal types of thermosensitive, itch sensitive, type C low-threshold mechanosensitive and nociceptive neurons with markedly different molecular and operational properties. Confirming previously anticipated major neuronal types, our results also classify and provide markers for new, functionally distinct subtypes. For example, our results suggest that itching during inflammatory skin diseases such as atopic dermatitis is linked to a distinct itch-generating type. We demonstrate single-cell RNA-seq as an effective strategy for dissecting sensory responsive cells into distinct neuronal types. The resulting catalog illustrates the diversity of sensory types and the cellular complexity underlying somatic sensation.

1,609 citations