Ghrelin is a peptide hormone produced and secreted in the stomach. Numerous studies over the past decade demonstrate its importance in food intake, body-weight regulation and glucose homeostasis. ...These effects are driven largely by the high expression of the ghrelin receptor (GHSR1a) in the hypothalamus. However, GHSR1a is also expressed in numerous extra-hypothalamic neuronal populations, suggesting that ghrelin has physiological functions besides those involved in metabolic functions. In this review, I focus on increasing evidence that ghrelin has important roles in extra-hypothalamic functions, including learning and memory, reward and motivation, anxiety and depression, and neuroprotection. Furthermore, I discuss how the recently demonstrated role of ghrelin in promoting survival during periods of caloric restriction could contribute to its inherent neuroprotective and neuromodulatory properties.
Ghrelin is a stomach hormone, secreted into the bloodstream, that initiates food intake by activating NPY/AgRP neurons in the hypothalamic acruate nucleus. This review focuses on recent evidence that ...details the mechanisms through which ghrelin activate receptors on NPY neurons and downstream signaling within NPY neurons. The downstream signaling involves a novel CaMKK-AMPK-CPT1-UCP2 pathway that enhances mitochondrial efficiency and buffers reactive oxygen species in order to maintain an appropriate firing response in NPY. Recent evidence that shows metabolic status affects ghrelin signaling in NPY is also described. In particular, ghrelin does not activate NPY neurons in diet-induced obese mice and ghrelin does not increase food intake. The potential mechanisms and implications of ghrelin resistance are discussed.
The primary task of white adipose tissue (WAT) is the storage of lipids. However, “beige” adipocytes also exist in WAT. Beige adipocytes burn fat and dissipate the energy as heat, but their abundance ...is diminished in obesity. Stimulating beige adipocyte development, or WAT browning, increases energy expenditure and holds potential for combating metabolic disease and obesity. Here, we report that insulin and leptin act together on hypothalamic neurons to promote WAT browning and weight loss. Deletion of the phosphatases PTP1B and TCPTP enhanced insulin and leptin signaling in proopiomelanocortin neurons and prevented diet-induced obesity by increasing WAT browning and energy expenditure. The coinfusion of insulin plus leptin into the CNS or the activation of proopiomelanocortin neurons also increased WAT browning and decreased adiposity. Our findings identify a homeostatic mechanism for coordinating the status of energy stores, as relayed by insulin and leptin, with the central control of WAT browning.
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•Insulin and leptin act synergistically on POMC neurons to promote WAT browning•Increased POMC-mediated WAT browning prevents diet-induced obesity•PTP1B and TCPTP attenuate leptin and insulin signaling in POMC neurons•Combined PTP1B and TCPTP deficiency in POMC neurons promotes white fat browning
Insulin and leptin act synergistically in POMC neurons in the hypothalamus to promote white fat browning, increasing thermogenesis and thereby contributing to maintaining energy homeostasis.
Ghrelin is a key signal driving energy seeking and storage in order to reverse energy deficit. In line with this view, the metabolic status of an organism predicts sensitivity to ghrelin, with ...fasting increasing and obesity decreasing ghrelin sensitivity. However, the mechanism responsible for controlling this sensitivity is unknown. In this issue of the JCI, Mani and colleagues show that plasma levels of plasma liver-enriched antimicrobial peptide-2 (LEAP2), a recently identified hormone that antagonizes the ghrelin receptor, are inversely correlated with those of plasma acyl-ghrelin under conditions of both energy deficit and energy surplus in mice and humans. Their results show that a fall in plasma LEAP2 during energy deficit facilitates the actions of acyl-ghrelin, whereas increased LEAP2 in obesity suppresses the actions of acyl-ghrelin. This important discovery helps reshape our understanding of ghrelin function and may provide a new approach to aiding weight maintenance after diet-induced weight loss.
Neural circuits influence food intake by responding to interoceptive hunger cues and/or hedonic cues. A new study utilizes a hunger discrimination behavioural task combined with opto- and ...chemo-genetic manipulation to identify hunger and non-hunger sensing neural circuits driving food intake.
Neural circuits influence food intake by responding to interoceptive hunger cues and/or hedonic cues. A new study utilizes a hunger discrimination behavioural task combined with opto- and chemo-genetic manipulation to identify hunger and non-hunger sensing neural circuits driving food intake.
Ghrelin is a metabolic hormone that promotes energy conservation by regulating appetite and energy expenditure. Although some studies suggest that antagonizing ghrelin function attenuates body weight ...gain and glucose intolerance on a high calorie diet, there is little information about the metabolic actions of ghrelin in the obese state. In this review, we discuss the novel concept of obesity-induced central ghrelin resistance in neural circuits regulating behavior, and impaired ghrelin secretion from the stomach. Interestingly, weight loss restores ghrelin secretion and function, and we hypothesize that ghrelin resistance is a mechanism designed to protect a higher body weight set-point established during times of food availability, to maximize energy reserves during a time of food scarcity.
Hunger increases the motivation for calorie consumption, often at the expense of low‐taste appeal. However, the neural mechanisms integrating calorie‐sensing with increased motivation for calorie ...consumption remain unknown. Agouti‐related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus sense hunger, and the ingestion of caloric solutions promotes dopamine release in the absence of sweet taste perception. Therefore, we hypothesised that metabolic‐sensing of hunger by AgRP neurons would be essential to promote dopamine release in the nucleus accumbens in response to caloric, but not non‐caloric solutions. Moreover, we examined whether metabolic sensing in AgRP neurons affected taste preference for bitter solutions under conditions of energy need. Here we show that impaired metabolic sensing in AgRP neurons attenuated nucleus accumbens dopamine release in response to sucrose, but not saccharin, consumption. Furthermore, metabolic sensing in AgRP neurons was essential to distinguish nucleus accumbens dopamine response to sucrose consumption when compared with saccharin. Under conditions of hunger, metabolic sensing in AgRP neurons increased the preference for sucrose solutions laced with the bitter tastant, quinine, to ensure calorie consumption, whereas mice with impaired metabolic sensing in AgRP neurons maintained a strong aversion to sucrose/quinine solutions despite ongoing hunger. In conclusion, we demonstrate normal metabolic sensing in AgRP neurons drives the preference for calorie consumption, primarily when needed, by engaging dopamine release in the nucleus accumbens.
Although hunger increases calorie intake independent from taste, the exact mechanisms through which this occurs remain unknown. This study shows that hunger‐sensing neurons in the hypothalamus (AgRP neurons) are required to transmit hunger signals to dopamine release in the nucleus accumbens and drive the consumption of caloric solutions over non‐caloric solutions. The ability of AgRP neurons to sense caloric need during fasting also prioritises calorie consumption over taste, a strong selective advantage when faced with unpleasant tastes. A greater appreciation of how hunger and motivation pathways interact is essential to understand dysfunctional conditions, such as under and overeating, which reflect human conditions such as eating disorders and/or obesity.
Metformin is a widely prescribed drug used to treat type-2 diabetes, although recent studies show it has wide ranging effects to treat other diseases. Animal and retrospective human studies indicate ...that Metformin treatment is neuroprotective in Parkinson's Disease (PD), although the neuroprotective mechanism is unknown, numerous studies suggest the beneficial effects on glucose homeostasis may be through AMPK activation. In this study we tested whether or not AMPK activation in dopamine neurons was required for the neuroprotective effects of Metformin in PD. We generated transgenic mice in which AMPK activity in dopamine neurons was ablated by removing AMPK beta 1 and beta 2 subunits from dopamine transporter expressing neurons. These AMPK WT and KO mice were then chronically exposed to Metformin in the drinking water then exposed to MPTP, the mouse model of PD. Chronic Metformin treatment significantly attenuated the MPTP-induced loss of Tyrosine Hydroxylase (TH) neuronal number and volume and TH protein concentration in the nigrostriatal pathway. Additionally, Metformin treatment prevented the MPTP-induced elevation of the DOPAC:DA ratio regardless of genotype. Metformin also prevented MPTP induced gliosis in the Substantia Nigra. These neuroprotective actions were independent of genotype and occurred in both AMPK WT and AMPK KO mice. Overall, our studies suggest that Metformin's neuroprotective effects are not due to AMPK activation in dopaminergic neurons and that more research is required to determine how metformin acts to restrict the development of PD.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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