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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EResearch by the French physiologist Claude Bernard more than a century ago established the connection between the brain and the control of glucose levels, the main mechanism of glucose homeostasis and energy balance. Beginning with Professor Bernard\u0027s groundbreaking findings, This article discusses the history of hypothalamic research including his own current work on the impact of the hypothalamus on diabetes.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHyperglycemia\/Hypoglycemia\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EEndocrinology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Metabolic Syndrome\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHyperglycemia\/Hypoglycemia\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EResearch by the French physiologist Claude Bernard more than a century ago established the connection between the brain and the control of glucose levels, the main mechanism of glucose homeostasis and energy balance. Beginning with Professor Bernard\u0027s groundbreaking findings, Joel K. Elmquist, DVM, PhD, University of Texas Southwestern Medical Center, Dallas, Texas, USA, discussed the history of hypothalamic research including his own current work on the impact of the hypothalamus on diabetes.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe prevalence of diabetes is increasing at an alarming rate (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). Particularly troubling is the increasing rate among children, which is occurring hand-in-hand with the rising rate of obesity. Among youths aged 2 to 19 years, 31.8% are overweight and 16.9% are obese [Dabelea D et al. \u003Cem\u003EJAMA\u003C\/em\u003E 2014]. There is not an organ system in the body that is not adversely affected by the pathophysiology of diabetes; thus, this increase is truly a public health crisis, said Dr. Elmquist.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Increasing Prevalence of Type 2 Diabetes\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-93727936\u0022 data-figure-caption=\u0022Increasing Prevalence of Type 2 Diabetes\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14613\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-4\u0022 class=\u0022first-child\u0022\u003EIncreasing Prevalence of Type 2 Diabetes\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-5\u0022\u003EIn 1940, Hetherington and Ranson published a key paper showing that the hypothalamus was critical for regulating food intake, body weight, and glucose homeostasis in rats. These same pathways were also found to be operational in humans. The 1997 discovery that melanocortinergic neurons, particularly melanocortin-4 receptors (MC4R) [Farooqi IS et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2002], were associated with feeding and the agouti obesity syndrome in mice led to the identification of a genetics connection between obesity, the regulation of energy balance, and glucose homeostasis. Injection of recombinant human leptin in obese children with leptin deficiency produced sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia, confirming a relationship between phenotypic abnormalities and obesity in humans [Farooqi IS et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2002]. Further, children with MC4R deficiency have a distinct obesity syndrome that is defined by a correlation between the signaling properties of these mutant receptors and energy intake [Farooqi IS et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2003]. These observations affirmed research findings in mice and helped map out key pathways for diabetic pathology (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Pathways for Diabetic Pathophysiology\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-93727936\u0022 data-figure-caption=\u0022Pathways for Diabetic Pathophysiology\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14669\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-6\u0022 class=\u0022first-child\u0022\u003EPathways for Diabetic Pathophysiology\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EHT = hydroxytryptamine.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EAdapted from Elmquist JK, Marcus JN. \u003Cem\u003ENat Med\u003C\/em\u003E 2003.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-7\u0022\u003EThe current model of energy balance is viewed as a neuronal system in the brain that regulates energy intake, energy expenditure, and endogenous glucose production. The system senses and responds to input from hormonal and nutrient-related signals that promote energy homeostasis and the maintenance of blood glucose levels in the normal range. Defects in the system lead to obesity and type 2 diabetes mellitus (T2DM) [Schwartz MW, Porte D Jr. \u003Cem\u003EScience\u003C\/em\u003E 2005].\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EMuch attention has been focused on the melanocortin pathway in the brain and the peptide proopiomelanocortin (POMC) located in neurons of the hypothalamus, which act as endogenous ligands for MC4R. Pharmacologic manipulation of POMC gene expression could provide a potential way to combat obesity. For instance, \u03b1-MSH (melanocyte stimulating hormone), cleaved from a POMC precursor, decreases food intake, lowers body weight, and decreases blood sugar when given to animals. POMC neurons also activate leptin receptors and inhibit agouti-related peptides (AgRP), which positively influence feeding behavior.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EThe complexity of the POMC system led Dr. Elmquist and colleagues to try neuron-specific gene manipulation that allowed direct testing in awake, unrestrained mice, eg, deletion of genes expressing the Cre and flox genes. It is also possible to re-express genes in selected neurons, eg, the nucleus-specific re-expression of the ObR (leptin receptors that exhibit an obese phenotype). Mice with no ObR genes are prone to obesity, diabetes, infertility, and hypoactivity.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003ELeptin receptor re-expression with viral vectors in the hypothalamic arcuate nucleus (ARH) produces modest decreases in body weight and food intake. However, blood glucose levels are markedly improved, if not normalized (\u003Ca id=\u0022xref-fig-3-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003EFigure 3\u003C\/a\u003E) [Coppari R et al. \u003Cem\u003ECell Metab\u003C\/em\u003E 2005].\u003C\/p\u003E\u003Cdiv id=\u0022F3\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Leptin Receptor Re-expression in Hypothalamic Arcuate Nucleus Neurons\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-93727936\u0022 data-figure-caption=\u0022Leptin Receptor Re-expression in Hypothalamic Arcuate Nucleus Neurons\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 3.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F3.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F3.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 3.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F3.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14615\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 3.\u003C\/span\u003E \n            \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003ELeptin Receptor Re-expression in Hypothalamic Arcuate Nucleus Neurons\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003EARH = hypothalamic arcuate nucleus.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-4\u0022\u003EReproduced from Coppari R et al. The hypothalamic arcuate nucleus: A key site for mediating leptin\u0027s effects on glucose homeostasis and locomotor activity. \u003Cem\u003ECell Metab\u003C\/em\u003E 2005;1:63\u201372. With permission from Elsevier.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-12\u0022\u003EAnother model can assess the role of leptin receptors in chemically identified neurons. In this model, endogenous leptin action on its receptor, prevented by a LoxP-flanked transcription blocker (loxTB), is then reactivated by Cre recombinase. Re-expression of leptin receptors only in POMC neurons in the ARH did not reduce food intake but partially normalized energy expenditure and modestly reduced body weight. Thus, it was concluded that leptin receptors in POMC neurons are not a major regulator of body weight or feeding [Berglund ED et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2012]. However, leptin receptor re-expression in POMC neurons normalized blood glucose and ameliorated hepatic insulin resistance, hyperglucagonemia, and dyslipidemia. Thus, in the absence of obesity control, leptin can regulate glucose homeostasis (\u003Ca id=\u0022xref-fig-4-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F4\u0022\u003EFigure 4\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F4\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F4.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Leptin Receptor Re-expression in POMC Neurons\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-93727936\u0022 data-figure-caption=\u0022Leptin Receptor Re-expression in POMC Neurons\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 4.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F4.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F4.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 4.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F4.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14617\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 4.\u003C\/span\u003E \n            \u003Cp id=\u0022p-13\u0022 class=\u0022first-child\u0022\u003ELeptin Receptor Re-expression in POMC Neurons\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-5\u0022\u003ELEPR = leptin receptor; loxTB = LoxP-flanked transcription blocker; POMC-cre = cre recombinase in POMC neurons.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-6\u0022\u003EReproduced from Berglund ED et al. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2012;122(3):1000\u20131009. With permission from the American Society for Clinical Investigation.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-14\u0022\u003EBrainstem neurons that control food intake and autonomic neurons that control energy expenditure are not the same. MC4Rs re-expressed by cholinergic (autonomic) neurons normalize hepatic glucose production but this is not true for MC4Rs expressed by brainstem neurons [Rossi J et al. \u003Cem\u003ECell Metab\u003C\/em\u003E 2011]. In addition, deleting MC4Rs in both sympathetic and parasympathetic cholinergic neurons increases food intake, the incidence of obesity, and impairs hepatic glucose homeostasis in mice (\u003Ca id=\u0022xref-fig-5-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F5\u0022\u003EFigure 5\u003C\/a\u003E) [Berglund ED et al. \u003Cem\u003ENat Neurosci\u003C\/em\u003E 2014].\u003C\/p\u003E\u003Cdiv id=\u0022F5\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F5.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Melanocortin-4 Receptors in Autonomic Neurons Regulate Hepatic Glucose Production\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-93727936\u0022 data-figure-caption=\u0022Melanocortin-4 Receptors in Autonomic Neurons Regulate Hepatic Glucose Production\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 5.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F5.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F5.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 5.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F5.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14670\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 5.\u003C\/span\u003E \n            \u003Cp id=\u0022p-15\u0022 class=\u0022first-child\u0022\u003EMelanocortin-4 Receptors in Autonomic Neurons Regulate Hepatic Glucose Production\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-7\u0022\u003EMC4R = melanocortin 4 receptors; controls = intact MC4R signaling; MC4R flox \u00d7 Chat-cre = selective deletion of MC4R in cholinergic pre-ganglionic neurons; MC4R-null = ectopic ablation of MC4R; HGP = hepatic glucose production.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-8\u0022\u003EReproduced from Berglund ED et al. Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. \u003Cem\u003ENat Neurosci\u003C\/em\u003E 2014;17(7):911\u2013914. With permission from the Nature Publishing Group.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-16\u0022\u003EThus, there are neurons (paraventricular nucleus of the hypothalamus) in the forebrain that express MC4Rs downstream of POMC and AgRP neurons and that are key regulators of food intake; sympathetic neurons regulate energy expenditure, glucose homeostasis, and hepatic insulin sensitivity, whereas vagus neurons regulate insulin secretion.\u003C\/p\u003E\u003Cp id=\u0022p-17\u0022\u003EBesides leptin signaling, brain serotonin contributes substantially to the regulation of feeding and energy expenditure. Young adult mice with a targeted mutation of the serotonin 5-HT\u003Csub\u003E2C\u003C\/sub\u003E receptor gene consume more food despite normal responses to exogenous leptin administration. Mutant mice also respond more to high-fat feeding, leading to hyperglycemia without hyperlipidemia. The obesity drug fenfluramine increases serotonin release and inhibits reuptake, leading to significant weight loss. Mice lacking serotonin receptors are less sensitive to the satiating effects of d-fenfluramine 3 mg\/kg compared with mice with intact serotonin receptors (\u003Ca id=\u0022xref-fig-6-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F6\u0022\u003EFigure 6\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F6\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F6.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Blunted Satiety Response to d-Fenfluramine in Mice Lacking Serotonin Receptors\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-93727936\u0022 data-figure-caption=\u0022Blunted Satiety Response to d-Fenfluramine in Mice Lacking Serotonin Receptors\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 6.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F6.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F6.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 6.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/19\/9\/F6.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14671\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 6.\u003C\/span\u003E \n            \u003Cp id=\u0022p-18\u0022 class=\u0022first-child\u0022\u003EBlunted Satiety Response to d-Fenfluramine in Mice Lacking Serotonin Receptors\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-9\u0022\u003EGray bars = mice lacking serotonin receptors; blue bars = mice with serotonin receptors.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-10\u0022\u003EReproduced from Vickers SP et al. Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice. \u003Cem\u003EPsychopharmacology\u003C\/em\u003E 1999;143:309\u2013314. With permission from Springer Verlag.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-19\u0022\u003EInformation generated from this research is translating into clinical studies. Leptin deficiency contributes to insulin resistance and is associated with severe lipodystrophy. Leptin-replacement has been shown to improve glycemic control and decrease triglyceride levels in patients with lipodystrophy and leptin deficiency [Oral EA et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2002]. The selective serotonin 2C receptor agonist, lorcaserin, when given to obese individuals, is associated with a modest but significant weight loss compared with placebo [Smith SR et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2010]. This class of compounds might be useful for the treatment of diabetes as well as obesity.\u003C\/p\u003E\u003Cp id=\u0022p-20\u0022\u003EClaude Bernard was the first to think about how the brain controls complex metabolic pathways, particularly in the liver. Two hundred years later, he was more right than he knew. Going forward, a better understanding of these mechanisms will be very important for combating the growing epidemic of diabetes.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/19\/9.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzp2gp\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzp2gp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}