Publications
70 results found
Izzi-Engbeaya C, Ma Y, Buckley NW, et al., 2020, Effects of corticosterone within the hypothalamic arcuate nucleus on food intake and body weight in male rats, Molecular Metabolism, Vol: 36, Pages: 1-7, ISSN: 2212-8778
BackgroundObesity is a major cause of morbidity and mortality. Few weight-reducing medications are available, and these have limited efficacy. Cushing’s Syndrome (caused by elevated glucocorticoid levels) and obesity have similar metabolic features. Though circulating glucocorticoid levels are not elevated in obesity, tissue-specific glucocorticoid levels have been implicated in the development of the metabolic phenotype of obesity. Tissue glucocorticoid levels are regulated by 11β-hydroxysteroid dehydrogenase type1 (11βHSD1), which increases the local concentration of active glucocorticoids by production of corticosterone from 11-dehydrocorticosterone. 11βHSD1 is expressed in the hypothalamic arcuate nucleus (ARC), a major weight and appetite-regulating centre, and therefore represents a target for novel anti-obesity therapeutic agents.ObjectivesTo investigate the effect of chronic alterations of ARC corticosterone levels (mediated by 11βHSD1) on food intake and body weight in adult male rats.MethodsRecombinant adeno-associated virus bearing sense 11βHSD1 (rAAV-S11βHSD1) and small interfering 11βHSD1 (rAAV-si11βHSD1) respectively were stereotactically injected into the ARC (bilaterally) of adult male Wistar rats. rAAV-GFP was injected into control groups of male Wistar rats. Food intake and body weight were measured three times a week for 70 days. Terminal brain, plasma and intrascapular brown adipose tissue (iBAT) samples were taken for measurement of mRNA expression and hormone levels.ResultsCompared to controls, rAAV-S11βHSD1 injection resulted in higher ARC corticosterone levels, hyperphagia and increased weight gain. Conversely, rAAV-si11βHSD1 injection (compared to controls) resulted in lower ARC corticosterone levels, higher iBAT uncoupling protein-1 mRNA expression and less weight gain despite similar food intake.ConclusionsTherefore, ARC corticosterone, regulated by 11βHSD1, may play a role in fo
Ma Y, Ratnasabapathy R, De Backer I, et al., 2020, Glucose in the hypothalamic paraventricular nucleus regulates GLP-1 release, JCI insight, Vol: 5, ISSN: 2379-3708
Glucokinase (GK) is highly expressed in the hypothalamic paraventricular nucleus (PVN); however, its role is currently unknown. We found that GK in the PVN acts as part of a glucose-sensing mechanism within the PVN that regulates glucose homeostasis by controlling glucagon-like peptide 1 (GLP-1) release. GLP-1 is released from enteroendocrine L cells in response to oral glucose. Here we identify a brain mechanism critical to the release of GLP-1 in response to oral glucose. We show that increasing expression of GK or injection of glucose into the PVN increases GLP-1 release in response to oral glucose. On the contrary, decreasing expression of GK or injection of nonmetabolizable glucose into the PVN prevents GLP-1 release. Our results demonstrate that gluco-sensitive GK neurons in the PVN are critical to the response to oral glucose and subsequent release of GLP-1.
Gardiner JV, Ma Y, Ratnasabapathy R, et al., 2018, Hypothalamic arcuate nucleus glucokinase regulates insulin secretion and glucose homeostasis, Diabetes, Obesity and Metabolism, Vol: 20, Pages: 2246-2254, ISSN: 1462-8902
AimsGlucokinase (GK) serves as a glucose sensor in several tissues including glucose‐sensitive neurons of the arcuate nucleus within the hypothalamus. We have previously demonstrated a role for arcuate GK in the regulation of food and glucose intake. However, its role in the regulation of glucose homeostasis is less clear. We therefore sought to investigate the role of arcuate GK in the regulation of glucose homeostasis.Materials and MethodsRecombinant adeno‐associated virus expressing either GK or an antisense GK construct was used to alter GK activity specifically in the hypothalamic arcuate nucleus. GK activity in this nucleus was also increased by stereotactic injection of the GK activator, compound A. The effect of altered arcuate nucleus GK activity on glucose homeostasis was subsequently investigated using glucose and insulin tolerance tests.ResultsIncreased GK activity specifically within the arcuate nucleus increased insulin secretion and improved glucose tolerance in rats during oral glucose tolerance tests. Decreased GK activity in this nucleus reduced insulin secretion and increased glucose levels during the same tests. Insulin sensitivity was not affected in either case. The effect of arcuate nucleus glucokinase was maintained in a model of type 2 diabetes.ConclusionsThese results demonstrate a role for arcuate nucleus GK in systemic glucose homeostasis.
Cork SC, Eftekhar A, Mirza KB, et al., 2018, Extracellular pH monitoring for use in closed-loop vagus nerve stimulation, Journal of Neural Engineering, Vol: 15, Pages: 1-11, ISSN: 1741-2552
Objective: Vagal nerve stimulation (VNS) has shown potential benefits for obesity treatment; however, current devices lack physiological feedback, which limit their efficacy. Changes in extracellular pH (pHe) have shown to be correlated with neural activity, but have traditionally been measured with glass microelectrodes, which limit their in vivo applicability. Approach. Iridium oxide has previously been shown to be sensitive to fluctuations in pH and is biocompatible. Iridium oxide microelectrodes were inserted into the subdiaphragmatic vagus nerve of anaesthetised rats. Introduction of the gut hormone cholecystokinin (CCK) or distension of the stomach was used to elicit vagal nerve activity. Main results. Iridium oxide microelectrodes have sufficient pH sensitivity to readily detect changes in pHe associated with both CCK and gastric distension. Furthermore, a custom-made Matlab script was able to use these changes in pHe to automatically trigger an implanted VNS device. Significance. This is the first study to show pHe changes in peripheral nerves in vivo. In addition, the demonstration that iridium oxide microelectrodes are sufficiently pH sensitive as to measure changes in pHe associated with physiological stimuli means they have the potential to be integrated into closed-loop neurostimulating devices.
Ma Y, Ratnasabapathy R, Gardiner J, 2017, Carbohydrate craving: not everything is sweet, Current Opinion in Clinical Nutrition and Metabolic Care, Vol: 20, Pages: 261-265, ISSN: 1363-1950
Purpose of review: Cravings for carbohydrates have been known about for hundreds of years but the mechanisms behind itwere unclear. This review will highlight recent advances in our knowledge of mechanisms to detectcarbohydrates in the diet.Recent findings: Recent work has begun to identify the physiological mechanisms by which carbohydrates andglucose are detected and how this drives their intake. Recently, evidence has been found forsystems that regulate carbohydrate and glucose intake via taste, hedonic, and homeostaticpathways.Summary: Identification of the physiological mechanisms that regulate carbohydrate intake will allow a betterunderstanding of how their intake is regulated and responds to changes in dietary intake. Such anunderstanding will be a key for developing a more rational approach to the development of successfulweight loss diets.
Hameed S, Patterson M, Dhillo W, et al., 2017, Thyroid hormone receptor beta in the ventromedial hypothalamus is essential for the physiological regulation of food intake and body weight, Cell Reports, Vol: 19, Pages: 2202-2209, ISSN: 2211-1247
The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRβ) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRβ in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRβ in the VMH as a major physiological regulator of food intake and energy homeostasis.
Cegla J, Jones BJ, Gardiner JV, et al., 2017, RAMP2 influences glucagon receptor pharmacology via trafficking and signaling, Endocrinology, Vol: 158, Pages: 2680-2693, ISSN: 0013-7227
Endogenous satiety hormones provide an attractive target for obesity drugs. Glucagon causes weight loss by reducing food intake and increasing energy expenditure. To further understand the cellular mechanisms by which glucagon and related ligands activate the glucagon receptor (GCGR), we investigated the interaction of the GCGR with receptor activity modifying protein (RAMP)2, a member of the family of receptor activity modifying proteins. We used a combination of competition binding experiments, cell surface enzyme-linked immunosorbent assay, functional assays assessing the Gαs and Gαq pathways and β-arrestin recruitment, and small interfering RNA knockdown to examine the effect of RAMP2 on the GCGR. Ligands tested were glucagon; glucagonlike peptide-1 (GLP-1); oxyntomodulin; and analog G(X), a GLP-1/glucagon coagonist developed in-house. Confocal microscopy was used to assess whether RAMP2 affects the subcellular distribution of GCGR. Here we demonstrate that coexpression of RAMP2 and the GCGR results in reduced cell surface expression of the GCGR. This was confirmed by confocal microscopy, which demonstrated that RAMP2 colocalizes with the GCGR and causes significant GCGR cellular redistribution. Furthermore, the presence of RAMP2 influences signaling through the Gαs and Gαq pathways, as well as recruitment of β-arrestin. This work suggests that RAMP2 may modify the agonist activity and trafficking of the GCGR, with potential relevance to production of new peptide analogs with selective agonist activities.
Gardiner JV, bloom SR, Hussain S, et al., 2016, INSIGHTS INTO THE ROLE OF NEURONAL GLUCOKINASE, American Journal of Physiology-Endocrinology and Metabolism, Vol: 311, Pages: E42-E55, ISSN: 1522-1555
Glucokinase is a key component of the neuronal glucose-sensing mechanism and is expressed in brain regions that control a range of homeostatic processes. In this review, we detail recently identified roles for neuronal glucokinase in glucose homeostasis and counter-regulatory responses to hypoglycaemia and in regulating appetite. We describe clinical implications from these advances in our knowledge especially for developing novel treatments for diabetes and obesity. Further research required to extend our knowledge and help our efforts to tackle the diabetes and obesity epidemics are suggested.
Ma Y, Bloom SR, Gardiner JV, 2015, Arcuate nucleus glucokinase and dietary glucose intake, Oncotarget, Vol: 6, Pages: 19926-19927, ISSN: 1949-2553
Hu MH, Li XF, McCausland B, et al., 2015, Relative importance of the arcuate and anteroventral periventricular kisspeptin neurons in control of puberty and reproductive function in female rats, Endocrinology, Vol: 156, Pages: 2619-2631, ISSN: 1945-7170
McGavigan AK, O'Hara HC, Amin A, et al., 2015, L-cysteine suppresses ghrelin and reduces appetite in rodents and humans, INTERNATIONAL JOURNAL OF OBESITY, Vol: 39, Pages: 447-455, ISSN: 0307-0565
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- Citations: 28
Hussain S, Richardson E, Ma Y, et al., 2015, Glucokinase activity in the arcuate nucleus regulates glucose intake., J Clin Invest, Vol: 125, Pages: 337-349
The brain relies on a constant supply of glucose, its primary fuel, for optimal function. A taste-independent mechanism within the CNS that promotes glucose delivery to the brain has been postulated to maintain glucose homeostasis; however, evidence for such a mechanism is lacking. Here, we determined that glucokinase activity within the hypothalamic arcuate nucleus is involved in regulation of dietary glucose intake. In fasted rats, glucokinase activity was specifically increased in the arcuate nucleus but not other regions of the hypothalamus. Moreover, pharmacologic and genetic activation of glucokinase in the arcuate nucleus of rodent models increased glucose ingestion, while decreased arcuate nucleus glucokinase activity reduced glucose intake. Pharmacologic targeting of potential downstream glucokinase effectors revealed that ATP-sensitive potassium channel and P/Q calcium channel activity are required for glucokinase-mediated glucose intake. Additionally, altered glucokinase activity affected release of the orexigenic neurotransmitter neuropeptide Y in response to glucose. Together, our results suggest that glucokinase activity in the arcuate nucleus specifically regulates glucose intake and that appetite for glucose is an important driver of overall food intake. Arcuate nucleus glucokinase activation may represent a CNS mechanism that underlies the oft-described phenomena of the "sweet tooth" and carbohydrate craving.
McGowan BM, Minnion JS, Murphy KG, et al., 2014, Relaxin-3 stimulates the neuro-endocrine stress axis via corticotrophin-releasing hormone, JOURNAL OF ENDOCRINOLOGY, Vol: 221, Pages: 337-346, ISSN: 0022-0795
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- Citations: 29
Beale KE, Kinsey-Jones JS, Gardiner JV, et al., 2014, The Physiological Role of Arcuate Kisspeptin Neurons in the Control of Reproductive Function in Female Rats, ENDOCRINOLOGY, Vol: 155, Pages: 1091-1098, ISSN: 0013-7227
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- Citations: 36
Beale KEL, Gardiner JV, Bewick GA, et al., 2013, Peripheral administration of prokineticin 2 potently reduces food intake and body weight in mice via the brainstem, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 168, Pages: 403-410, ISSN: 0007-1188
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- Citations: 26
Patterson M, Bloom SR, Gardiner JV, 2011, Ghrelin and appetite control in humans-Potential application in the treatment of obesity, PEPTIDES, Vol: 32, Pages: 2290-2294, ISSN: 0196-9781
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- Citations: 51
McGowan BMC, Minnion JS, Murphy KG, et al., 2010, Central and peripheral administration of human relaxin-2 to adult male rats inhibits food intake, DIABETES OBESITY & METABOLISM, Vol: 12, Pages: 1090-1096, ISSN: 1462-8902
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- Citations: 16
Boughton CK, Patterson M, Bewick GA, et al., 2010, Alarin stimulates food intake and gonadotrophin release in male rats, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 161, Pages: 601-613, ISSN: 0007-1188
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- Citations: 36
Gardiner JV, Beale KE, Roy D, et al., 2010, Cerebellin1 is a novel orexigenic peptide, DIABETES OBESITY & METABOLISM, Vol: 12, Pages: 883-890, ISSN: 1462-8902
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- Citations: 9
Gardiner JV, Campbell D, Patterson M, et al., 2010, The Hyperphagic Effect of Ghrelin Is Inhibited in Mice by a Diet High in Fat, GASTROENTEROLOGY, Vol: 138, Pages: 2468-U338, ISSN: 0016-5085
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- Citations: 33
Richardson E, Hussain SS, Counsell JR, et al., 2010, The Role of Ventromedial Hypothalamic Glucose-Sensing Neurons during Glucoprivation., 92nd Meeting and Expo of the Endocrine Society (ENDO 2010), Publisher: ENDOCRINE SOC, ISSN: 0163-769X
Boughton CK, Patterson M, Tadross JA, et al., 2010, The Novel Neuropeptide Alarin Stimulates Food Intake and the Reproductive Axis in Male Rats., 92nd Meeting and Expo of the Endocrine Society (ENDO 2010), Publisher: ENDOCRINE SOC, ISSN: 0163-769X
Leavy EM, Gardiner JV, Richardson E, et al., 2010, The Role of Neuropeptide Y within the Hypothalamic Dorsomedial Nucleus in the Regulation of Energy Homeostasis., 92nd Meeting and Expo of the Endocrine Society (ENDO 2010), Publisher: ENDOCRINE SOC, ISSN: 0163-769X
Gardiner JV, Bataveljic A, Patel NA, et al., 2009, Prokineticin 2 Is a Hypothalamic Neuropeptide That Potently Inhibits Food Intake, Diabetes, Vol: 59, Pages: 397-406, ISSN: 0012-1797
OBJECTIVE Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis.RESEARCH DESIGN AND METHODS We investigated the effect of nutritional status on hypothalamic PK2 expression and effects of PK2 on the regulation of food intake by intracerebroventricular (ICV) injection of PK2 and anti-PK2 antibody. Subsequently, we investigated the potential mechanism of action by determining sites of neuronal activation after ICV injection of PK2, the hypothalamic site of action of PK2, and interaction between PK2 and other hypothalamic neuropeptides regulating energy homeostasis. To investigate PK2's potential as a therapeutic target, we investigated the effect of chronic administration in lean and obese mice.RESULTS Hypothalamic PK2 expression was reduced by fasting. ICV administration of PK2 to rats potently inhibited food intake, whereas anti-PK2 antibody increased food intake, suggesting that PK2 is an anorectic neuropeptide. ICV administration of PK2 increased c-fos expression in proopiomelanocortin neurons of the arcuate nucleus (ARC) of the hypothalamus. In keeping with this, PK2 administration into the ARC reduced food intake and PK2 increased the release of α-melanocyte–stimulating hormone (α-MSH) from ex vivo hypothalamic explants. In addition, ICV coadministration of the α-MSH antagonist agouti-related peptide blocked the anorexigenic effects of PK2. Chronic peripheral administration of PK2 reduced food and body weight in lean and obese mice.CONCLUSIONS This is the first report showing that PK2 has a role in appetite regulation and its anorectic effect is mediated partly via the melanocortin system.
Dhillo WS, Bewick GA, White NE, et al., 2009, The thyroid hormone derivative 3-iodothyronamine increases food intake in rodents, DIABETES OBESITY & METABOLISM, Vol: 11, Pages: 251-260, ISSN: 1462-8902
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- Citations: 39
Bewick GA, Kent A, Campbell D, et al., 2009, Mice With Hyperghrelinemia Are Hyperphagic and Glucose Intolerant and Have Reduced Leptin Sensitivity, Diabetes, Vol: 58, Pages: 840-846, ISSN: 0012-1797
Smith KL, Gardiner JV, Ward HL, et al., 2008, Overexpression of CART in the PVN increases food intake and weight gain in rats, OBESITY, Vol: 16, Pages: 2239-2244, ISSN: 1930-7381
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- Citations: 38
McGowan BM, Stanley SA, Donovan J, et al., 2008, Relaxin-3 stimulates the hypothalamic-pituitary-gonadal axis, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, Vol: 295, Pages: E278-E286, ISSN: 0193-1849
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- Citations: 64
Gardiner JV, Jayasena CN, Bloom SR, 2008, Gut hormones: A weight off your mind, JOURNAL OF NEUROENDOCRINOLOGY, Vol: 20, Pages: 834-841, ISSN: 0953-8194
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- Citations: 31
Gardiner J, Bloom S, 2008, Ghrelin gets its GOAT, CELL METABOLISM, Vol: 7, Pages: 193-194, ISSN: 1550-4131
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- Citations: 9
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