Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity

Steculorum, Sophie M.; Timper, Katharina; Ruud, Linda Engström; Evers, Nadine; Paeger, Lars; Bremser, Stephan; Kloppenburg, Peter

doi:10.1016/j.celrep.2017.01.047

Cited by 39 publications

(28 citation statements)

References 41 publications

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“…These findings are consistent with the outcome of a recent study that reported improved insulin sensitivity in HFD mice lacking P2Y 6 R in whole body or specifically in AgRP neurons of the hypothalamus (20). The role of P2Y 6 R in controlling energy balance was also highlighted in a study demonstrating that increased plasma uridine levels in obesity increased hypothalamic UDP synthesis to activate AgRP P2Y 6 R, thereby increasing food intake (11).…”

Section: R Might Lead Tosupporting

confidence: 89%

Lack of Adipocyte Purinergic P2Y₆Receptor Greatly Improves Whole Body Glucose Homeostasis

Jain

Pydi

Toti

et al. 2020

Preprint

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Uridine diphosphate (UDP)-activated purinergic receptor P2Y 6 (P2Y 6 R) plays a crucial role in controlling energy balance through central mechanisms. However, P2Y 6 R's roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising novel finding that adipocyte-specific deletion of P2Y 6 R protects mice from dietinduced obesity, improving glucose tolerance and insulin sensitivity with reduced systemic inflammation. These changes were associated with reduced JNK signaling, and enhanced expression and activity of PPARα affecting downstream PGC1α levels leading to beiging of white fat. In contrast, P2Y 6 R deletion in skeletal muscle reduced glucose uptake resulting in impaired glucose homeostasis. Interestingly, whole body P2Y 6 R KO mice showed metabolic improvements similar to those observed with mice lacking P2Y 6 R only in adipocytes. Our findings provide compelling evidence that P2Y 6 R antagonists may prove useful for the treatment of obesity and type 2 diabetes.

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Section: R Might Lead Tosupporting

confidence: 89%

Lack of Adipocyte Purinergic P2Y₆Receptor Greatly Improves Whole Body Glucose Homeostasis

Jain

Pydi

Toti

et al. 2020

Preprint

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“…At molecular level, several genes in AgRP neurons have been associated with this regulation of whole-body glucose homeostasis. For instance, the deletion of purinergic receptor 6 (P2Y6) specifically in AgRP neurons, improved systemic insulin sensitivity in obese mice [41] and similar results have been observed when the transcription factor activating transcription factor 4 (ATF4) was deleted specifically in AgRP neurons [42].…”

Section: Agrp Neurons and Glucose Metabolismsupporting

confidence: 55%

Targeting AgRP neurons to maintain energy balance: Lessons from animal models

Zagmutt

Mera

Soler‐Vázquez

et al. 2018

Biochemical Pharmacology

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The current obesity epidemic is a major worldwide health and economic burden. In the modern environment, an increase in the intake of high-fat and high-sugar foods plays a crucial role in the development of obesity by disrupting the mechanisms governing food intake and energy balance. Food intake and whole-body energy balance are regulated by the central nervous system through a sophisticated neuronal network located mostly in the hypothalamus. In particular, the hypothalamic arcuate nucleus (ARC) is a fundamental center that senses hormonal and nutrient-related signals informing about the energy state of the organism. The ARC contains two small, defined populations of neurons with opposite functions: anorexigenic proopiomelanocortin (POMC)-expressing neurons and orexigenic Agouti-related protein (AgRP)-expressing neurons. AgRP neurons, which also co-produce neuropeptide Y (NPY) and γ-Aminobutyric acid (GABA), are involved in an increase in hunger and a decrease in energy expenditure. In this review, we summarize the key findings from the most common animal models targeting AgRP neurons and the tools used to discern the role of this specific neuronal population in the control of peripheral metabolism, appetite, feeding-related behavior, and other complex behaviors. We also discuss how knowledge gained from these studies has revealed new pathways and key proteins that could be potential therapeutic targets to reduce appetite and food addictions in obesity and other diseases.

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“…In the context of obesity, uridine levels are elevated in the circulation (Steculorum et al, 2015), indicating that the uridine/UDP system might be another mechanism that promotes the vicious cycle of increased weight gain along with exaggerated food intake. Consistent with this model, AgRP-neuron-specific P2Y6-deficient mice are protected from high-fat-diet-induced adiposity and insulin resistance (Steculorum et al, 2017) (see poster, Obese fasting state).…”

Section: New Perspectives In Cns-dependent Control Of Feeding Behaviomentioning

confidence: 80%

Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

Timper

Brüning

2017

Disease Models &Amp; Mechanisms

Self Cite

580

545

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The ‘obesity epidemic’ represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed.

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Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity

Cited by 39 publications

References 41 publications

Lack of Adipocyte Purinergic P2Y₆Receptor Greatly Improves Whole Body Glucose Homeostasis

Lack of Adipocyte Purinergic P2Y₆Receptor Greatly Improves Whole Body Glucose Homeostasis

Targeting AgRP neurons to maintain energy balance: Lessons from animal models

Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

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Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity

Cited by 39 publications

References 41 publications

Lack of Adipocyte Purinergic P2Y6Receptor Greatly Improves Whole Body Glucose Homeostasis

Lack of Adipocyte Purinergic P2Y6Receptor Greatly Improves Whole Body Glucose Homeostasis

Targeting AgRP neurons to maintain energy balance: Lessons from animal models

Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

Contact Info

Product

Resources

About

Lack of Adipocyte Purinergic P2Y₆Receptor Greatly Improves Whole Body Glucose Homeostasis

Lack of Adipocyte Purinergic P2Y₆Receptor Greatly Improves Whole Body Glucose Homeostasis