Die Another Day: A Painless Path to Longevity

Riera et al. identify a neuroendocrine circuit that controls longevity and the age-dependent onset of metabolic decline via the pain-transducing channel TRPV1. Thus, pharmacological inhibition of TRPV1 may provide a new approach to treat not only metabolic disorders but also a broader range of age-related pathologies

Sweet Mitochondrial Dynamics in VMH Neurons

The ventromedial nucleus of the hypothalamus (VMH) is a central region known to maintain glucose homeostasis. Toda et al. (2016) unravel a new mechanism underlying VMH-dependent regulation of systemic glucose homeostasis via uncoupling protein 2 (UCP2)-mediated control of mitochondrial dynamics and activation of glucose-excited neurons

Neuronal control of peripheral insulin sensitivity and glucose metabolism

The central nervous system (CNS) has an important role in the regulation of peripheral insulin sensitivity and glucose homeostasis. Research in this dynamically developing field has progressed rapidly due to techniques allowing targeted transgenesis and neurocircuitry mapping, which have defined the primary responsive neurons, associated molecular mechanisms and downstream neurocircuitries and processes involved. Here we review the brain regions, neurons and molecular mechanisms by which the CNS controls peripheral glucose metabolism, particularly via regulation of liver, brown adipose tissue and pancreatic function, and highlight the potential implications of these regulatory pathways in type 2 diabetes and obesity

The paradox of neuronal insulin action and resistance in the development of aging-associated diseases

During past decades, ever-increasing life expectancy, despite the development of a sedentary lifestyle and altered eating habits, has led to a dramatic parallel increase in the prevalence of age-related diseases such as type 2 diabetes mellitus (T2DM) and neurodegenerative disorders. Converging evidence from animal and human studies has indicated that insulin resistance in the central nervous system (CNS) is observed in both T2DM and neurodegenerative disorders such as Alzheimer's disease (AD), leading to the hypothesis that impaired neuronal insulin action might be a unifying pathomechanism in the development of both diseases. This assumption, however, is in striking contrast to the evolutionary conserved, protective role of impaired insulin/insulin-like growth factor 1 signaling (IIS) in aging and in protein aggregation-associated diseases, such as AD. Thus, this review summarizes our current understanding of the physiological role of insulin action in various regions of the CNS to regulate neuronal function, learning, and memory, and to control peripheral metabolism. We also discuss mechanisms and clinical outcomes of neuronal insulin resistance and address the seeming paradox of how impaired neuronal IIS can protect from the development of neurodegenerative disorders. (C) 2014 The Alzheimer's Association. All rights reserved

AgRP neuronal activity across feeding-related behaviours

AgRP neurons trigger one of the most potent orexigenic responses and are both necessary and sufficient for feeding. Recent technical advances for monitoring in vivo neuronal activity have revisited a previously well-established model of AgRP neurons' feeding regulatory effects. Our current understanding of AgRP neurons has increased in complexity and revealed a fine-tuned regulation of their activity dynamics across the whole sequence of feeding-related behaviours. This review focuses on recent studies that refined and re-evaluated our understanding of the regulatory principles and behavioural effects of AgRP circuits. We aim to cover major discoveries on the dynamic regulation of AgRP neuronal activity by exteroceptive and interoceptive food-related cues, their pleiotropic effects in feeding and whole-body homeostasis, and the associated AgRP circuits. The function and regulation of AgRP neuron will be sequentially discussed across the temporal series of behavioural and physiological changes occurring during the appetitive (food craving and foraging), the anticipatory (discovery of food-predicting cues), and the consummatory/post-ingestive phase of feeding (calorie ingestion)

Hypothalamic UDP Increases in Obesity and Promotes Feeding via P2Y6-Dependent Activation of AgRP Neurons

Activation of orexigenic AgRP-expressing neurons in the arcuate nucleus of the hypothalamus potently promotes feeding, thus defining new regulators of AgRP neuron activity could uncover potential novel targets for obesity treatment. Here, we demonstrate that AgRP neurons express the purinergic receptor 6 (P2Y6), which is activated by uridine-diphosphate (UDP). In vivo, UDP induces ERK phosphorylation and cFos expression in AgRP neurons and promotes action potential firing of these neurons in brain slice recordings. Consequently, central application of UDP promotes feeding, and this response is abrogated upon pharmacologic or genetic inhibition of P2Y6 as well as upon pharmacogenetic inhibition of AgRP neuron activity. In obese animals, hypothalamic UDP content is elevated as a consequence of increased circulating uridine concentrations. Collectively, these experiments reveal a potential regulatory pathway in obesity, where peripheral uridine increases hypothalamic UDP concentrations, which in turn can promote feeding via PY6-dependent activation of AgRP neurons

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

Uridine-diphosphate (UDP) and its receptor P2Y6 have recently been identified as regulators of AgRP neurons. UDP promotes feeding via activation of P2Y6 receptors on AgRP neurons, and hypothalamic UDP concentrations are increased in obesity. However, it remained unresolved whether inhibition of P2Y6 signaling pharmacologically, globally, or restricted to AgRP neurons can improve obesity-associated metabolic dysfunctions. Here, we demonstrate that central injection of UDP acutely promotes feeding in diet-induced obese mice and that acute pharmacological blocking of CNS P2Y6 receptors reduces food intake. Importantly, mice with AgRP-neuron-restricted inactivation of P2Y6 exhibit reduced food intake and fat mass as well as improved systemic insulin sensitivity with improved insulin action in liver. Our results reveal that P2Y6 signaling in AgRP neurons is involved in the onset of obesity-associated hyperphagia and systemic insulin resistance. Collectively, these experiments define P2Y6 as a potential target to pharmacologically restrict both feeding and systemic insulin resistance in obesity