IMAGING IN ENDOCRINOLOGY: The use of functional MRI to study the endocrinology of appetite

Salem, Victoria; Dhillo, Waljit S.

doi:10.1530/eje-14-0716

Cited by 15 publications

(10 citation statements)

References 73 publications

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“…Our findings are also distinct from those of other studies, using the same antibody, reporting that there were no GLP-1 receptors in the parietal cortex of non-human primates [10]. Although we did not see changes in the hypothalamus in response to food cues while participants were taking liraglutide, this may be due to the limitations of MRI, due partly to the size of this structure and partly to its proximity to the sinuses, which creates artefacts [18]. As far as identification of GLP-1 in the human brain, Drucker and Asa described in 1988 GLP-1 (also known as GCG ) mRNA-positive neurons in the region of dorsal motor nucleus of the vagus nerve in the medulla oblongata [19].…”

Section: Discussioncontrasting

confidence: 99%

“…This may be due to differences in terms of control of eating between rodents and humans; in the latter the homeostatic control of eating is often overridden by more complex cortical systems regulating the rewarding value of food [18]. This may also be a limitation of fMRI in general, as the hypothalamus is difficult to detect with typical fMRI measures due in part to its small size and in part to its proximity to the sinuses, which create artefacts [18]. …”

Section: Discussionmentioning

confidence: 99%

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GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial

et al. 2016

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Aims/hypothesis Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome). Methods In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrollment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (fMRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. Results Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide −0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation. Conclusions/interpretation For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial

et al. 2016

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“…Human functional neuroimaging studies converge with animal studies in identifying subcortical and cortical brain structures that are involved in the control of eating. Typically, these studies localize regions that respond differently to food and non-food stimuli, to hunger and satiety, and in obese and normal-weight women (Morris and Dolan, 2001;Wang et al, 2004;Small and Prescott, 2005;Stoeckel et al, 2008;Schur et al, 2009;Salem and Dhillo, 2015). Both animal and human receptor expression studies suggest that reproductive hormones may affect the function of these regions.…”

Section: Central Mechanismsmentioning

confidence: 99%

Ovarian hormones and obesity

Leeners

Geary

Tobler

et al. 2017

Human Reproduction Update

273

182

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The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health.

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“…12 Correspondingly, distinct MRI approaches have been used to demonstrate abnormalities in obesity for both the brain's macrostructure (eg, cortical thickness and regional volume) 14,15 and functionality. [16][17][18] For example, functional MRI (fMRI) studies in adults with obesity suggest a disrupted hypothalamic response to glucose ingestion characterized by an attenuated response after glucose intake. 19,20 It is unknown if children with obesity present the same response pattern to glucose ingestion.…”

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confidence: 99%

Initial evidence for hypothalamic gliosis in children with obesity by quantitative T2 MRI and implications for blood oxygen‐level dependent response to glucose ingestion

et al. 2018

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Summary Objective In adults, hypothalamic gliosis has been documented using quantitative T2 neuroimaging, whereas functional magnetic resonance imaging (fMRI) has shown a defective hypothalamic response to nutrients. No studies have yet evaluated these hypothalamic abnormalities in children with obesity. Methods Children with obesity and lean controls underwent quantitative MRI measuring T2 relaxation time, along with continuous hypothalamic fMRI acquisition to evaluate early response to glucose ingestion. Results Children with obesity (N = 11) had longer T2 relaxation times, consistent with gliosis, in the mediobasal hypothalamus (MBH) compared to controls (N = 9; P = 0.004). Moreover, there was a highly significant group*region interaction (P = 0.002), demonstrating that signs of gliosis were specific to MBH and not to reference regions. Longer T2 relaxation times correlated with measures of higher adiposity, including visceral fat percentage (P = 0.01). Mean glucose‐induced hypothalamic blood oxygen‐level dependent signal change did not differ between groups (P = 0.11). However, mean left MBH T2 relaxation time negatively correlated with glucose‐induced hypothalamic signal change (P < 0.05). Conclusion Imaging signs of hypothalamic gliosis were present in children with obesity and positively associated with more severe adiposity. Children with the strongest evidence for gliosis showed the least activation after glucose ingestion. These initial findings suggest that the hypothalamus is both structurally and functionally affected in childhood obesity.

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IMAGING IN ENDOCRINOLOGY: The use of functional MRI to study the endocrinology of appetite

Cited by 15 publications

References 73 publications

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial

Ovarian hormones and obesity

Initial evidence for hypothalamic gliosis in children with obesity by quantitative T2 MRI and implications for blood oxygen‐level dependent response to glucose ingestion

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