Their approach involves using designer receptors exclusively activated by designer drugs DREADD technology to activate Gcg -expressing neurons. Acute treatment with CNO did not impact insulin levels or skeletal muscle glucose uptake.
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And while CNO modestly decreased gluconeogenesis in mice on a standard rodent diet, this effect did not translate into a measurable impact on glucose tolerance. Interestingly, decreased food intake was magnified when the experiment was repeated in mice on a high-fat diet HFD , to the extent that chronic CNO treatment caused a decrease in body weight.
It still remains to be seen whether these discrepancies arise due to differences in methodology i. The results of Gaykema and coworkers 8 add a new dimension to understanding the role of proglucagon peptides in the brain, a topic of continued translational importance, as new drugs that are co-agonists of both GLP-1R and glucagon receptors are being explored as treatments for metabolic diseases. The recapitulation of some, but not all, of the effects previously attributed to GLP-1 in the CNS raises interesting questions that should drive the field forward.
In fact, based on the data presented, it can only be assumed that the effect of CNO to reduce food intake involves GLP-1, or Gcg -associated products. Nonetheless, the Gcg -DREADD model provides a firm base from which to address a tractable neural system that likely plays a significant role in systemic metabolism.
Some of the findings of Gaykema et al. For example, it would be very advantageous if activation of these nerves can cause satiety without malaise or visceral illness, since nausea is currently the limiting side effect of GLP-1R agonists in clinical use. This could provide greater or more lasting weight loss, as CNS administration of GLP-1 to animals 9 and peripheral GLP-1 administration to humans 10 increase circulating glucocorticoids as well as satiety, responses with opposing impacts on body weight.
These findings are consistent with previous work showing potentiation of GLP-1 effects on feeding by leptin 11 , a peptide increased in obesity. This interaction suggests a role for GLP-1 to mitigate the effects of metabolic stress in the CNS, potentially as a mechanism to restore homeostasis. A similar hypothesis has been proposed for understanding the role of GLP-1 produced in other tissues. This broad framing of GLP-1 actions may provide some predictive utility in understanding Gcg -encoded peptides in the three regions where they are produced.
The contribution of Gaykema and colleagues presented here provides a tangible means to move ahead in the study of the least-understood of these regions, the brain. Reference information: J Clin Invest. See the related article at Activation of murine pre-proglucagon—producing neurons reduces food intake and body weight.
Go to JCI Insight. First published February 20, - Version history. Clamp studies in mice showed that rises in peripheral insulin promote hepatic STAT3 phosphorylation in a time-dependent fashion Intriguingly, insulin failed to induce STAT3 phosphorylation in cultured hepatocytes 29 , suggesting that insulin mediates this effect independent of its hepatic signaling. The importance of hepatic STAT3 was further shown in mice with inducible insulin receptor inactivation, either in the whole body or in peripheral tissues only Mice with brain insulin receptor inactivation had worse hyperglycemia and failed to increase hepatic STAT3 phosphorylation or up-regulate IL-6 expression.
Furthermore, control mice given chronic ICV insulin had increased fat mass and adipose tissue lipoprotein lipase expression This work highlights the importance of central insulin in regulating peripheral glucose and lipid metabolism via hepatic STAT3 activation.
Other important work has established specific features of the signaling pathways whereby central insulin suppresses EGP in rodents. ICV insulin infusion failed to suppress EGP in mice lacking hepatic Irs1 and Irs2 double knock-out mice during hyperinsulinemic-euglycemic pancreatic clamps In addition, agouti-related peptide AgRP -expressing neurons of the arcuate nucleus of the hypothalamus were identified as the specific neurons responsive to central insulin and driving suppression of EGP in mice This was confirmed by additional studies in mice establishing the key role of insulin action in AgRP neurons in suppressing EGP 33 , as opposed to POMC neurons in which constitutive PI3K activation led to hyperphagia and diet-induced obesity in female mice 33 , Conversely, hypothalamic S6 kinase seems to have an inhibitory effect on hypothalamic insulin action.
After only 1 day of high fat diet, the ability of hypothalamic insulin to suppress EGP was blocked, an effect likely mediated by hypothalamic S6 kinase activation The relevance of central insulin action to the treatment of diabetes has been a subject of extensive study, with some animal models suggesting that impaired central insulin action contributes to the metabolic defects of diabetes. Enhancement of central insulin action via hypothalamic overexpression of IRS-2 or a downstream mediator of PI3K action improved the glucose-lowering effect of peripheral insulin by 2-fold The benefit of central insulin action in improving peripheral glucose metabolism was shown both in the acute setting and over several days of insulin therapy, suggesting both acute and chronic roles for hypothalamic insulin signaling in diabetes treatment Furthermore, diabetic rats receiving ICV infusions of insulin or insulin plus glucose for 4 weeks had decreased food intake and body weight and reduced EGP during hyperinsulinemic clamps This work highlighted the crucial role of central insulin on whole body glucose and nutrient handling in rats, opening the possibility of future diabetes treatments directed at central targets.
A key area of controversy has been translating evidence for central regulation of EGP from rodents to the physiology of larger mammals. Short duration pancreatic clamp studies in conscious dogs failed to show an acute impact on EGP when insulin delivery to the head was increased 4-fold Further work in dogs confirmed the ability of ICV insulin infusion to increase hepatic STAT3 phosphorylation and suppress hepatic gluconeogenic enzyme expression Although glucose production was not affected in this acute setting, net hepatic glucose output did slowly decrease over the course of these clamps.
Given the reduction in gluconeogenic enzyme gene expression, longer duration studies might have revealed an effect on EGP. Of note, the rodent studies discussed above were of longer duration and in some cases involved chronic models. Indeed, although the maximal effects of insulin on tissue signaling are seen shortly after administration 42 , an extended duration of about 5 h of hyperinsulinemia is needed to demonstrate its maximal whole body effects on glucose handling 43 , highlighting the potential importance of more prolonged central signaling on the regulation of glucose production.
Importantly, no studies to date have evaluated the time-dependent effect of CNS insulin on glucose production in rodents, and such studies would add important insights to the field.
Furthermore, it is possible that some metabolic endpoints may be rapidly impacted by central pathways 44 , whereas others may require more prolonged central pathway activation to manifest their full effects. Fatty acids are another key modulator of EGP, and accumulating evidence shows that the hypothalamus senses circulating nutrients, including fatty acids, with consequent effects on food intake and whole body glucose handling ICV infusion of the long-chain fatty acid LCFA oleic acid in rats led to rapid reductions in food intake, gluconeogenic enzyme expression, and EGP, whereas ICV infusion of a short chain fatty acid had no effect on these parameters Central effects of LCFA infusion were completely abolished after only a few days of high fat feeding, highlighting the potential for dysregulation of central monitoring of nutrient intake in the pathogenesis of obesity and insulin resistance Furthermore, inhibition of LCFA breakdown via selective inhibition of hypothalamic carnitine palmitoyltransferase CPT1 also led to decreased food intake and EGP in rats, highlighting the role of the hypothalamus as a nutrient sensor and the role of LCFAs as a signal of nutrient abundance Of note, hypothalamic CPT1 inhibition in overfed rats restored hypothalamic lipid sensing and suppression of EGP, suggesting potential therapeutic avenues in obese and overfed models Furthermore, in rats, hypothalamic K ATP channels are activated by central lipid fluxes, and efferent vagal input from the brainstem to the liver is required for hypothalamic lipids to impact expression of gluconeogenic enzymes and EGP Thus, hypothalamic K ATP channels were established as a common pathway for central insulin, glucose, and fatty acid sensing in rat models.
Some of the molecular mechanisms of hypothalamic K ATP channel lipid sensing were later clarified; hypothalamic protein kinase C PKC activation was necessary for central lipid administration to modulate EGP in rats Conversely, central insulin also seems to modulate peripheral lipid metabolism because central insulin administration restrains lipolysis in white adipose tissue, whereas mice lacking central insulin receptors have unrestrained white adipose tissue lipolysis Thus, a complex interplay between central and peripheral lipid metabolism has been established in rodent models.
Extensive studies suggest that the CNS, specifically the hypothalamus, is a sensor of overall nutrient status, modulating food intake and glucose metabolism Malonyl-CoA, the intermediate molecule in fatty acid biosynthesis, is a hypothalamic indicator of whole body nutritional status in mice 54 and rats The mammalian target of rapamycin mTOR is also an important hypothalamic fuel sensor in rats, colocalizing with anorexigenic POMC neurons and increasing in response to both central leucine and leptin administration to decrease food intake and body weight Additionally, constitutive hypothalamic expression of AMPK leads to increased food intake and body weight, whereas its suppression has an anorexigenic effect Indeed, hypothalamic AMPK is suppressed in response to central insulin, glucose, and leptin in mice, and stimulated in response to ICV infusion of the orexigenic agouti-related protein This evidence supports the ability of central nutrient sensing to affect whole body glucose handling and energy balance.
Since the identification of the murine obese ob gene and its product, leptin 59 — 61 , extensive work has demonstrated the central effects of leptin on whole body glucose and nutrient metabolism. Initial studies suggested that leptin mediates its effects on food intake and body weight at least partly via its ability to suppress expression of hypothalamic neuropeptide Y, an orexigenic molecule 62 , Like glucose and insulin, leptin hyperpolarized hypothalamic K ATP channels in neurons from lean, but not obese, rats In vivo , the central effects of leptin in rats were dependent on hypothalamic STAT3 signaling 65 , Indeed, the ability of systemic leptin to activate hypothalamic STAT3 was abolished in mice fed a high fat diet for 15 weeks, suggesting a mechanism for leptin resistance The central effects of leptin also appear to be mediated at least in part via PI3K-dependent pathways, again demonstrating similarities with the hypothalamic insulin signaling pathway 70 , Of note, at least some of the hypothalamic actions of leptin depend on melanocortin receptor activation, particularly its central effects on EGP 15 , 72 , and loss of hypothalamic leptin signaling is sufficient to promote obesity or T2DM 65 , Furthermore, low doses of ICV leptin improved insulin resistance in lipodystrophic mice, whereas similar doses given peripherally were ineffective Additionally, mice lacking hypothalamic POMC neuron receptors for insulin and leptin are insulin-resistant The therapeutic potential of central leptin to regulate glucose fluxes in models of obesity and insulin resistance was highlighted by the observation that central leptin inhibited glucose production in rats with hepatic insulin resistance following short term high fat feeding The presence of glucose-sensing neurons and insulin receptors in the human brain is well documented 9 , 77 , and recent evidence has demonstrated a potential role for central regulation of EGP.
Because diazoxide markedly inhibits pancreatic insulin secretion 79 , the pancreatic clamp technique allowed us to examine the extrapancreatic effects of diazoxide. Of note, complementary studies in rats 78 showed that diazoxide crosses the blood-brain barrier and confirmed the suppression of EGP during euglycemic pancreatic clamp studies following oral diazoxide, along with decreases in glucose 6-phosphatase G6Pase and phosphoenolpyruvate carboxykinase PEPCK expression and increased hepatic STAT3 phosphorylation.
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Together, these studies strongly suggest that hypothalamic K ATP channels regulate EGP, at least in part, in humans as well as in rodents. Consistent with the above work, a number of other studies suggest that the brain plays a regulatory role in glucose homeostasis in humans. Human subjects with an activating variant of the Kir6.
E23K homozygotes underwent oral glucose tolerance tests and hyperinsulinemic-euglycemic clamp studies, showing reduced insulin secretion but enhanced insulin sensitivity The authors hypothesized that as insulin resistance develops later in life, the effects of reduced insulin secretion are manifested by development of T2DM.
Another study of subjects with Type 1 diabetes T1DM also supports a potential clinically important role for central K ATP channels: metabolic control improved in T1DM subjects after a 6-month course of low dose diazoxide, with initial improvement after just 3 months of therapy, despite no measurable effect on insulin secretion Although the study was not designed to clarify the precise time course of the central effects of diazoxide on whole body glucose handling, the results suggest that diazoxide exerted its beneficial metabolic effects via activation of central pathways.
Studies of extrapancreatic effects of glucagon-like peptide GLP-1 also support a role for the brain in regulating peripheral glucose metabolism. Sandoval et al. In healthy humans, Prigeon et al. There was no effect on peripheral glucose uptake. Several brain imaging studies have implied that the brain serves as a metabolic sensor impacting whole body energy homeostasis in humans.
Functional MRI scans detecting blood oxygen level-dependent signals showed hypothalamic signaling changes in response to glucose infusions 86 — These changes were diminished or absent in obese 89 and T2DM subjects In addition, a link between CNS insulin and peripheral glucose metabolism was suggested by studies of intranasal insulin. Insulin effectively crosses the blood-brain barrier and appears in the CNS in significant concentrations within 30 min of intranasal administration, without significant elevations in circulating insulin levels Therefore, intranasal insulin enables examination of central insulin effects on peripheral metabolism in humans.
Benedict et al. The same group subsequently reported reduced body weight, body fat, and leptin levels in healthy male subjects following 8 weeks of intranasal insulin administration as compared with placebo Interestingly, the above effects were not observed in human female subjects, consistent with noted gender differences in peripheral responses to central insulin administration in some rodent studies 94 , Thus, supporting previous work in animal models, a growing body of evidence strongly suggests that central pathways play a key regulatory role in glucose and lipid homeostasis in humans.
Given the growing global diabetes epidemic, identifying new therapeutic targets is imperative. The paucity of human data concerning regulation of glucose homeostasis highlights this as an important area of future research with the potential to substantially impact the clinical outcomes of people with diabetes.
Frontiers | CNS Control of Glucose Metabolism: Response to Environmental Challenges | Neuroscience
This work was also supported by a grant from the American Diabetes Association. You'll be in good company. Journal of Lipid Research.
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DREADDing proglucagon neurons: a fresh look at metabolic regulation by the brain
Increased generation of neuronal progenitors after ischemic injury in the aged adult human forebrain. Machler, P. In vivo evidence for a lactate gradient from astrocytes to neurons. Maddock, R. Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study. Psychiatry 14, — Manczak, M. Mangia, S.
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