Role of orexins in the central and peripheral regulation of glucose homeostasis: Evidences &amp; mechanisms

Rani, Monika; Kumar, Rohit; Krishan, Pawan

doi:10.1016/j.npep.2018.02.002

Cited by 23 publications

(10 citation statements)

References 52 publications

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“…Recent studies have also reported involvement of the hypothalamic neuropeptide orexin in the brain regulation of glucose metabolism. Indeed, central administration of orexin A during the night-time awake period first elevates blood glucose levels and subsequently lowers daytime glycaemia in normal and diabetic db/db mice by bidirectional regulation of HGP relayed by the autonomic nervous system [29,30]. Collectively, these observations support the hypothesis that the control of glucose homeostasis results from complex and highly coordinated interactions between the brain and the pancreatic islets.…”

Section: Discussionmentioning

confidence: 52%

The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis

et al. 2022

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Aims/hypothesis 26RFa (pyroglutamilated RFamide peptide [QRFP]) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localised in the hypothalamus. In this study we investigated whether 26RFa neurons are involved in the hypothalamic regulation of glucose homeostasis. Methods 26Rfa +/+ , 26Rfa -/and insulin-deficient male C57Bl/6J mice were used in this study. Mice received an acute intracerebroventricular (i.c.v.) injection of 26RFa, insulin or the 26RFa receptor (GPR103) antagonist 25e and were subjected to IPGTTs, insulin tolerance tests, acute glucose-stimulated insulin secretion tests and pyruvate tolerance tests (PTTs). Secretion of 26RFa by hypothalamic explants after incubation with glucose, leptin or insulin was assessed. Expression and quantification of the genes encoding 26RFa, agouti-related protein, the insulin receptor and GPR103 were evaluated by quantitative reverse transcription PCR and RNAscope in situ hybridisation. Results Our data indicate that i.c.v.-injected 26RFa induces a robust antihyperglycaemic effect associated with an increase in insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26Rfa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26Rfa are mainly localised in the lateral hypothalamic area, that they co-express the gene encoding the insulin receptor and that insulin induces the expression of 26Rfa in these neurons. Concurrently, the central antihyperglycaemic effect of insulin is abolished in the presence of a GPR103 antagonist and in 26RFa-deficient mice. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. Conclusion/interpretationWe have identified a novel mechanism in the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system, and we provide evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

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Section: Discussionmentioning

confidence: 52%

The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis

et al. 2022

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“…Recent studies also report an implication of the hypothalamic neuropeptide orexin in the brain regulation of glucose metabolism. Indeed, central administration of orexin A during the night-time awake period firstly elevates blood glucose levels and subsequently lowers daytime glycemia in normal and diabetic db/db mice via a bidirectional regulation of glucose hepatic production relayed by the autonomic nervous system (32, 33). Collectively, these observations support the new concept claiming that the control of glucose homeostasis results from a complex and highly coordinated interactions between the brain and the pancreatic islets.…”

Section: Discussionmentioning

confidence: 99%

Identification of a discrete neuronal circuit that relays insulin signaling into the brain to regulate glucose homeostasis

Mehdi

Takhlidjt

Devere

et al. 2021

Preprint

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26RFa (QRFP) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localized in the hypothalamus. In the present study, we have investigated whether the 26RFa neurons may be involved in the hypothalamic regulation of glucose homeostasis. Our data indicate that 26RFa, i.c.v. injected, induces a robust antihyperglycemic effect associated with an increase of insulin production by the pancreatic islets. In addition, we found that insulin strongly stimulates 26RFa expression and secretion by the hypothalamus. RNAscope experiments revealed that neurons expressing 26RFa in the lateral hypothalamic area and the ventromedial hypothalamic nucleus also express the insulin receptor and that insulin induces the expression of 26RFa in these neurons. Concurrently, we show that the central antihyperglycemic effect of insulin is abolished in presence of a 26RFa receptor (GPR103) antagonist as well as in mice deficient for 26RFa. Finally, our data indicate that the hypothalamic 26RFa neurons are not involved in the central inhibitory effect of insulin on hepatic glucose production, but mediate the central effects of the hormone on its own peripheral production. To conclude, in the present study we have identified a novel actor of the hypothalamic regulation of glucose homeostasis, the 26RFa/GPR103 system and we provide the evidence that this neuronal peptidergic system is a key relay for the central regulation of glucose metabolism by insulin.

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“…Orexins, also known as hypocretins, have been suggested to regulate wakefulness, feeding, and metabolic homeostasis[ 60 ]. A study found that orexin-A level was elevated in patients with schizophrenia treated with antipsychotics, particularly in those taking fewer obesogenic antipsychotics[ 61 ].…”

Section: Mechanism Underlying Weight Gain and Metabolic Disturbances Due To Antipsychotic Drugsmentioning

confidence: 99%

Metabolic disturbances associated with antipsychotic drug treatment in patients with schizophrenia: State-of-the-art and future perspectives

Chang¹,

Goh²,

Lu³

2021

WJP

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Metabolic disturbances and obesity are major cardiovascular risk factors in patients with schizophrenia, resulting in a higher mortality rate and shorter life expectancy compared with those in the general population. Although schizophrenia and metabolic disturbances may share certain genetic or pathobiological risks, antipsychotics, particularly those of second generation, may further increase the risk of weight gain and metabolic disturbances in patients with schizophrenia. This review included articles on weight gain and metabolic disturbances related to antipsychotics and their mechanisms, monitoring guidelines, and interventions. Nearly all antipsychotics are associated with weight gain, but the degree of the weight gain varies considerably. Although certain neurotransmitter receptor-binding affinities and hormones are correlated with weight gain and specific metabolic abnormalities, the precise mechanisms underlying antipsychotic-induced weight gain and metabolic disturbances remain unclear. Emerging evidence indicates the role of genetic polymorphisms associated with antipsychotic-induced weight gain and antipsychotic-induced metabolic disturbances. Although many guidelines for screening and monitoring antipsychotic-induced metabolic disturbances have been developed, they are not routinely implemented in clinical care. Numerous studies have also investigated strategies for managing antipsychotic-induced metabolic disturbances. Thus, patients and their caregivers must be educated and motivated to pursue a healthier life through smoking cessation and dietary and physical activity programs. If lifestyle intervention fails, switching to another antipsychotic drug with a lower metabolic risk or adding adjunctive medication to mitigate weight gain should be considered. Antipsychotic medications are essential for schizophrenia treatment, hence clinicians should monitor and manage the resulting weight gain and metabolic disturbances.

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Role of orexins in the central and peripheral regulation of glucose homeostasis: Evidences & mechanisms

Cited by 23 publications

References 52 publications

The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis

The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis

Identification of a discrete neuronal circuit that relays insulin signaling into the brain to regulate glucose homeostasis

Metabolic disturbances associated with antipsychotic drug treatment in patients with schizophrenia: State-of-the-art and future perspectives

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