Signaling pathways in obesity: mechanisms and therapeutic interventions

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 28, 2022

Abstract Obesity is a complex, chronic disease and global public health challenge. Characterized by excessive fat accumulation in the body, obesity sharply increases risk of several diseases, such as type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver linked to lower life expectancy. Although lifestyle intervention (diet exercise) has remarkable effects on weight management, achieving long-term success at loss extremely challenging, prevalence continues rise worldwide. Over past decades, pathophysiology been extensively investigated, an increasing number signal transduction pathways have implicated obesity, making it possible fight more effective precise way. In this review, we summarize recent advances pathogenesis from both experimental clinical studies, focusing signaling their roles regulation food intake, glucose homeostasis, adipogenesis, thermogenesis, inflammation. We also discuss current anti-obesity drugs, well compounds trials, that target these signals. The evolving knowledge may shed light future direction research, move into new era precision medicine.

Language: Английский

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Arcuate Nucleus-Dependent Regulation of Metabolism—Pathways to Obesity and Diabetes Mellitus

Endocrine Reviews, Journal Year: 2021, Volume and Issue: 43(2), P. 314 - 328

Published: Sept. 7, 2021

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

Language: Английский

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POMC neuronal heterogeneity in energy balance and beyond: an integrated view

Nature Metabolism, Journal Year: 2021, Volume and Issue: 3(3), P. 299 - 308

Published: Feb. 25, 2021

Language: Английский

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The physiological control of eating: signals, neurons, and networks

Physiological Reviews, Journal Year: 2021, Volume and Issue: 102(2), P. 689 - 813

Published: Sept. 6, 2021

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

Language: Английский

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Acts of appetite: neural circuits governing the appetitive, consummatory, and terminating phases of feeding

Nature Metabolism, Journal Year: 2022, Volume and Issue: 4(7), P. 836 - 847

Published: July 25, 2022

Language: Английский

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Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism

Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(3), P. 473 - 493

Published: Feb. 20, 2024

Abstract Agouti-related peptide (AgRP)-expressing and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combine non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP POMC for comparing metabolic responses male female mice with simultaneous activation of inhibition isolated or neurons. We show that intake is regulated by the additive effect neuron inhibition, while systemic insulin sensitivity gluconeogenesis are differentially modulated isolated-versus-simultaneous regulation identify a neurocircuit engaging Npy1R-expressing paraventricular nucleus hypothalamus, where activated inhibited cooperate promote consumption activate Th + tractus solitarii. Collectively, these results unveil how precisely bidirectional interplay between neurocircuits.

Language: Английский

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AgRP neurons: Regulators of feeding, energy expenditure, and behavior

FEBS Journal, Journal Year: 2021, Volume and Issue: 289(8), P. 2362 - 2381

Published: Sept. 1, 2021

Neurons in the hypothalamic arcuate nucleus (ARC) that express agouti‐related peptide (AgRP) govern a critical aspect of survival: drive to eat. Equally important survival is timing at which food consumed—seeking or eating alleviate hunger face more pressing threat, like risk predation, clearly maladaptive. To ensure optimal prioritization behaviors within given environment, therefore, AgRP neurons must integrate signals internal need states with contextual environmental cues. In this state‐of‐the‐art review, we highlight recent advances extend our understanding neurons, including neural circuits they engage regulate feeding, energy expenditure, and behavior. We also discuss key findings illustrate how both classical feedback anticipatory feedforward neuronal population integration these may be disrupted excess. Finally, examine technical conceptual challenges facing field moving forward.

Language: Английский

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Sulforaphane reduces obesity by reversing leptin resistance

eLife, Journal Year: 2022, Volume and Issue: 11

Published: March 1, 2022

The ascending prevalence of obesity in recent decades is commonly associated with soaring morbidity and mortality rates, resulting increased health-care costs decreased quality life. A systemic state stress characterized by low-grade inflammation pathological formation reactive oxygen species (ROS) usually manifests obesity. transcription factor nuclear erythroid-derived 2-like 2 (NRF2) the master regulator redox homeostasis plays a critical role resolution inflammation. Here, we show that natural isothiocyanate potent NRF2 activator sulforaphane reverses diet-induced through predominantly, but not exclusively, NRF2-dependent mechanism requires functional leptin receptor signaling hyperleptinemia. Sulforaphane does reduce body weight or food intake lean mice induces an anorectic response when coadministered exogenous leptin. Leptin-deficient Lep ob/ob mutant Lepr db/db display resistance to weight-reducing effect sulforaphane, supporting conclusion antiobesity signaling. Furthermore, our results suggest skeletal muscle as most notable site action whose peripheral signals alleviate resistance. Transcriptional profiling six major metabolically relevant tissues highlights suppresses fatty acid synthesis while promoting ribosome biogenesis, reducing ROS accumulation, resolving inflammation, therefore representing unique transcriptional program leads protection from Our findings argue for clinical evaluation loss obesity-associated metabolic disorders.

Language: Английский

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A synaptic amplifier of hunger for regaining body weight in the hypothalamus

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(5), P. 770 - 785.e5

Published: March 24, 2023

Restricting caloric intake effectively reduces body weight, but most dieters fail long-term adherence to deficit and eventually regain lost weight. Hypothalamic circuits that control hunger drive critically determine weight; yet, how weight loss sculpts these motivate food consumption until is regained remains unclear. Here, we probe the contribution of synaptic plasticity in discrete excitatory afferents on hunger-promoting AgRP neurons. We reveal a crucial role for activity-dependent, remarkably long-lasting amplification activity originating from paraventricular hypothalamus thyrotropin-releasing (PVH

Language: Английский

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Neurobiology of eating behavior, nutrition, and health

Journal of Internal Medicine, Journal Year: 2023, Volume and Issue: 294(5), P. 582 - 604

Published: July 10, 2023

Eating behavior and food-related decision making are among the most complex of motivated behaviors, understanding neurobiology eating behavior, its developmental dynamics, is critical to advancing nutritional sciences public health. Recent advances from both human animal studies revealing that individual capacity make health-promoting food decisions varies based on biological physiological variation in signaling pathways regulate homeostatic, hedonic, executive functions; past exposures current life-stage; environment; complications chronic disease reinforce obese state. rate drives increased calorie intake represents an important opportunity lower rates consumption energy through product reformulation. Understanding behaviors nutrition context neuroscience can strengthen evidence base which dietary guidelines derived inform policies, practices, educational programs a way increases likelihood they adopted effective for reducing obesity other diet-related disease.

Language: Английский

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