Abstract
Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.
Key points
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Insulin crosses the blood–brain barrier via a saturable transport to bind to insulin receptors widely expressed throughout the brain; insulin signalling in the brain regulates systemic nutrient partitioning in animal models and humans.
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Brain insulin action controls appetite, adipose tissue lipolysis, hepatic triglyceride secretion and branched-chain amino acid metabolism, protecting the organism from ectopic lipid accumulation and lipotoxicity.
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The role of brain insulin in suppressing hepatic glucose production remains controversial.
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Overnutrition rapidly induces brain insulin resistance even before peripheral insulin signalling is impaired, implicating brain insulin resistance as a key culprit of metabolic disease and diabetes.
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Tools to assess brain insulin action in humans are limited and involve MRI techniques, PET, magnetoencephalography and electroencephalography.
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Pharmacological interventions to improve brain insulin signalling have therapeutic potential for metabolic disease, diabetes and non-alcoholic fatty liver disease; augmenting brain insulin signalling might be particularly beneficial in preventing lipotoxicity with a low risk of hypoglycaemia.
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References
Schnurr, T. M. et al. Obesity, unfavourable lifestyle and genetic risk of type 2 diabetes: a case-cohort study. Diabetologia 63, 1324–1332 (2020).
Ono, H. et al. Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J. Clin. Invest. 118, 2959–2968 (2008).
Scherer, T. et al. Short term voluntary overfeeding disrupts brain insulin control of adipose tissue lipolysis. J. Biol. Chem. 287, 33061–33069 (2012).
Brons, C. et al. Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men. J. Physiol. 587, 2387–2397 (2009).
Cornier, M. A., Bergman, B. C. & Bessesen, D. H. The effects of short-term overfeeding on insulin action in lean and reduced-obese individuals. Metabolism 55, 1207–1214 (2006).
Unger, J. W. & Betz, M. Insulin receptors and signal transduction proteins in the hypothalamo-hypophyseal system: a review on morphological findings and functional implications. Histol. Histopathol. 13, 1215–1224 (1998).
Werther, G. A. et al. Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology 121, 1562–1570 (1987).
Zhao, W. et al. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J. Biol. Chem. 274, 34893–34902 (1999).
Marks, J. L., Porte, D. Jr., Stahl, W. L. & Baskin, D. G. Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127, 3234–3236 (1990).
Bromander, S. et al. Cerebrospinal fluid insulin during non-neurological surgery. J. Neural Transm. 117, 1167–1170 (2010).
Wallum, B. J. et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J. Clin. Endocrinol. Metab. 64, 190–194 (1987).
Clarke, D. W., Mudd, L., Boyd, F. T. Jr., Fields, M. & Raizada, M. K. Insulin is released from rat brain neuronal cells in culture. J. Neurochem. 47, 831–836 (1986).
Kuwabara, T. et al. Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb. EMBO Mol. Med. 3, 742–754 (2011).
Mehran, A. E. et al. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab. 16, 723–737 (2012).
Mazucanti, C. H. et al. Release of insulin produced by the choroid plexis is regulated by serotonergic signaling. JCI Insight 4, e131682 (2019).
Banks, W. A. The source of cerebral insulin. Eur. J. Pharmacol. 490, 5–12 (2004).
Baura, G. D. et al. Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J. Clin. Invest. 92, 1824–1830 (1993).
Banks, W. A., Jaspan, J. B., Huang, W. & Kastin, A. J. Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin. Peptides 18, 1423–1429 (1997).
Pardridge, W. M., Eisenberg, J. & Yang, J. Human blood-brain barrier insulin receptor. J. Neurochem. 44, 1771–1778 (1985).
Schwartz, M. W. et al. Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport. J. Clin. Invest. 88, 1272–1281 (1991).
Banks, W. A., Owen, J. B. & Erickson, M. A. Insulin in the brain: there and back again. Pharmacol. Ther. 136, 82–93 (2012).
Heni, M. et al. Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans. Acta Diabetol. 51, 679–681 (2014).
Sartorius, T. et al. The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier? PLoS One 10, e0126804 (2015).
Stanley, M., Macauley, S. L. & Holtzman, D. M. Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence? J. Exp. Med. 213, 1375–1385 (2016).
Torres-Aleman, I. Toward a comprehensive neurobiology of IGF-I. Dev. Neurobiol. 70, 384–396 (2010).
Dyer, A. H., Vahdatpour, C., Sanfeliu, A. & Tropea, D. The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity. Neuroscience 325, 89–99 (2016).
Mielke, J. G. & Wang, Y. T. Insulin, synaptic function, and opportunities for neuroprotection. Prog. Mol. Biol. Transl Sci. 98, 133–186 (2011).
Gralle, M. The neuronal insulin receptor in its environment. J. Neurochem. 140, 359–367 (2017).
Fadel, J. R. & Reagan, L. P. Stop signs in hippocampal insulin signaling: the role of insulin resistance in structural, functional and behavioral deficits. Curr. Opin. Behav. Sci. 9, 47–54 (2016).
De Felice, F. G. Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J. Clin. Invest. 123, 531–539 (2013).
van der Heide, L. P., Kamal, A., Artola, A., Gispen, W. H. & Ramakers, G. M. Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. J. Neurochem. 94, 1158–1166 (2005).
Chiu, S. L., Chen, C. M. & Cline, H. T. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron 58, 708–719 (2008).
Kim, S. J. & Han, Y. Insulin inhibits AMPA-induced neuronal damage via stimulation of protein kinase B (Akt). J. Neural Transm. 112, 179–191 (2005).
Pelvig, D. P., Pakkenberg, H., Stark, A. K. & Pakkenberg, B. Neocortical glial cell numbers in human brains. Neurobiol. Aging 29, 1754–1762 (2008).
Blinkow, S. & Glezer, I. in The Human Brain in Figures and Tables (ed. Blinkow, F. G.) 237–253 (Plenum Press, 1968).
Garcia-Caceres, C. et al. Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166, 867–880 (2016).
Debons, A. F., Krimsky, I. & From, A. A direct action of insulin on the hypothalamic satiety center. Am. J. Physiol. 219, 938–943 (1970).
Hatfield, J. S., Millard, W. J. & Smith, C. J. Short-term influence of intra-ventromedial hypothalamic administration of insulin on feeding in normal and diabetic rats. Pharmacol. Biochem. Behav. 2, 223–226 (1974).
Strubbe, J. H. & Mein, C. G. Increased feeding in response to bilateral injection of insulin antibodies in the VMH. Physiol. Behav. 19, 309–313 (1977).
Woods, S. C. & Porte, D. Jr. The role of insulin as a satiety factor in the central nervous system. Adv. Metab. Disord. 10, 457–468 (1983).
Schwartz, M. W., Figlewicz, D. P., Baskin, D. G., Woods, S. C. & Porte, D. Jr. Insulin in the brain: a hormonal regulator of energy balance. Endocr. Rev. 13, 387–414 (1992).
Ajaya, B. & Haranath, P. S. Effects of insulin administered into cerebrospinal fluid spaces on blood glucose in unanaesthetized and anaesthetized dogs. Indian J. Med. Res. 75, 607–615 (1982).
Air, E. L., Benoit, S. C., Blake Smith, K. A., Clegg, D. J. & Woods, S. C. Acute third ventricular administration of insulin decreases food intake in two paradigms. Pharmacol. Biochem. Behav. 72, 423–429 (2002).
Woods, S. C., Lotter, E. C., McKay, L. D. & Porte, D. Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979).
Jessen, L., Clegg, D. J. & Bouman, S. D. Evaluation of the lack of anorectic effect of intracerebroventricular insulin in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R43–R50 (2010).
Benedict, C., Kern, W., Schultes, B., Born, J. & Hallschmid, M. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J. Clin. Endocrinol. Metab. 93, 1339–1344 (2008).
Hallschmid, M. et al. Intranasal insulin reduces body fat in men but not in women. Diabetes 53, 3024–3029 (2004).
Kaiyala, K. J., Prigeon, R. L., Kahn, S. E., Woods, S. C. & Schwartz, M. W. Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes 49, 1525–1533 (2000).
Stein, L. J. et al. Reduced effect of experimental peripheral hyperinsulinemia to elevate cerebrospinal fluid insulin concentrations of obese Zucker rats. Endocrinology 121, 1611–1615 (1987).
O’Hare, J. D., Zielinski, E., Cheng, B., Scherer, T. & Buettner, C. Central endocannabinoid signaling regulates hepatic glucose production and systemic lipolysis. Diabetes 60, 1055–1062 (2011).
Lindtner, C. et al. Binge drinking induces whole-body insulin resistance by impairing hypothalamic insulin action. Sci. Transl Med. 5, 170ra114 (2013).
Zhang, Z. Y., Dodd, G. T. & Tiganis, T. Protein tyrosine phosphatases in hypothalamic insulin and leptin signaling. Trends Pharmacol. Sci. 36, 661–674 (2015).
Cai, D. NFκB-mediated metabolic inflammation in peripheral tissues versus central nervous system. Cell Cycle 8, 2542–2548 (2009).
Goodyear, L. J. et al. Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J. Clin. Invest. 95, 2195–2204 (1995).
Posey, K. A. et al. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am. J. Physiol. Endocrinol. Metab. 296, E1003–E1012 (2009).
Won, J. C. et al. Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin. Obesity 17, 1861–1865 (2009).
Sims-Robinson, C. et al. The role of endoplasmic reticulum stress in hippocampal insulin resistance. Exp. Neurol. 277, 261–267 (2016).
Zhang, X. et al. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61–73 (2008).
Benoit, S. C. et al. Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents. J. Clin. Invest. 119, 2577–2589 (2009).
Scherer, T. et al. Brain insulin controls adipose tissue lipolysis and lipogenesis. Cell Metab. 13, 183–194 (2011).
Iwen, K. A. et al. Intranasal insulin suppresses systemic but not subcutaneous lipolysis in healthy humans. J. Clin. Endocrinol. Metab. 99, E246–E251 (2014).
Koch, L. et al. Central insulin action regulates peripheral glucose and fat metabolism in mice. J. Clin. Invest. 118, 2132–2147 (2008).
Scherer, T. et al. Insulin regulates hepatic triglyceride secretion and lipid content via signaling in the brain. Diabetes 65, 1511–1520 (2016).
Shin, A. C. et al. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab. 20, 898–909 (2014).
Pocai, A. et al. Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434, 1026–1031 (2005).
Obici, S., Feng, Z., Karkanias, G., Baskin, D. G. & Rossetti, L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat. Neurosci. 5, 566–572 (2002).
Obici, S., Zhang, B. B., Karkanias, G. & Rossetti, L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med. 8, 1376–1382 (2002).
Ruud, J., Steculorum, S. M. & Bruning, J. C. Neuronal control of peripheral insulin sensitivity and glucose metabolism. Nat. Commun. 8, 15259 (2017).
Vogt, M. C. & Bruning, J. C. CNS insulin signaling in the control of energy homeostasis and glucose metabolism - from embryo to old age. Trends Endocrinol. Metab. 24, 76–84 (2013).
Belgardt, B. F. & Bruning, J. C. CNS leptin and insulin action in the control of energy homeostasis. Ann. NY Acad. Sci. 1212, 97–113 (2010).
Williams, K. W. & Elmquist, J. K. From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat. Neurosci. 15, 1350–1355 (2012).
Padilla, S. L., Carmody, J. S. & Zeltser, L. M. Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nat. Med. 16, 403–405 (2010).
Xu, J. et al. Genetic identification of leptin neural circuits in energy and glucose homeostases. Nature 556, 505–509 (2018).
Orosco, M., Gerozissis, K., Rouch, C. & Nicolaidis, S. Feeding-related immunoreactive insulin changes in the PVN-VMH revealed by microdialysis. Brain Res. 671, 149–158 (1995).
Stein, L. J. et al. Immunoreactive insulin levels are elevated in the cerebrospinal fluid of genetically obese Zucker rats. Endocrinology 113, 2299–2301 (1983).
Hu, S. H., Jiang, T., Yang, S. S. & Yang, Y. Pioglitazone ameliorates intracerebral insulin resistance and tau-protein hyperphosphorylation in rats with type 2 diabetes. Exp. Clin. Endocrinol. Diabetes 121, 220–224 (2013).
Lai, Y. L., Smith, P. M., Lamm, W. J. & Hildebrandt, J. Sampling and analysis of cerebrospinal fluid for chronic studies in awake rats. J. Appl. Physiol. 54, 1754–1757 (1983).
Cashion, M. F., Banks, W. A. & Kastin, A. J. Sequestration of centrally administered insulin by the brain: effects of starvation, aluminum, and TNF-alpha. Hormones Behav. 30, 280–286 (1996).
Gordon, E. S. Non-esterified fatty acids in the blood of obese and lean subjects. Am. J. Clin. Nutr. 8, 740–747 (1960).
Mittendorfer, B., Magkos, F., Fabbrini, E., Mohammed, B. S. & Klein, S. Relationship between body fat mass and free fatty acid kinetics in men and women. Obesity 17, 1872–1877 (2009).
Gaidhu, M. P., Anthony, N. M., Patel, P., Hawke, T. J. & Ceddia, R. B. Dysregulation of lipolysis and lipid metabolism in visceral and subcutaneous adipocytes by high-fat diet: role of ATGL, HSL, and AMPK. Am. J. Physiol. Cell Physiol. 298, C961–C971 (2010).
Boden, G. Fatty acid-induced inflammation and insulin resistance in skeletal muscle and liver. Curr. Diab Rep. 6, 177–181 (2006).
Lafontan, M. & Langin, D. Lipolysis and lipid mobilization in human adipose tissue. Prog. Lipid Res. 48, 275–297 (2009).
Hers, H. G. & Hue, L. Gluconeogenesis and related aspects of glycolysis. Annu. Rev. Biochem. 52, 617–653 (1983).
Scherer, T. & Buettner, C. Yin and Yang of hypothalamic insulin and leptin signaling in regulating white adipose tissue metabolism. Rev. Endocr. Metab. Disord. 12, 235–243 (2011).
Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008).
Yore, M. M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014).
Diraison, F., Dusserre, E., Vidal, H., Sothier, M. & Beylot, M. Increased hepatic lipogenesis but decreased expression of lipogenic gene in adipose tissue in human obesity. Am. J. Physiol. Endocrinol. Metab. 282, E46–E51 (2002).
Roberts, R. et al. Markers of de novo lipogenesis in adipose tissue: associations with small adipocytes and insulin sensitivity in humans. Diabetologia 52, 882–890 (2009).
Mayas, M. D. et al. Inverse relation between FASN expression in human adipose tissue and the insulin resistance level. Nutr. Metab. 7, 3 (2010).
Eissing, L. et al. De novo lipogenesis in human fat and liver is linked to ChREBP-beta and metabolic health. Nat. Commun. 4, 1528 (2013).
Assimacopoulos-Jeannet, F., Brichard, S., Rencurel, F., Cusin, I. & Jeanrenaud, B. In vivo effects of hyperinsulinemia on lipogenic enzymes and glucose transporter expression in rat liver and adipose tissues. Metabolism 44, 228–233 (1995).
Chan, K. L. et al. Palmitoleate reverses high fat-induced proinflammatory macrophage polarization via AMP-activated Protein Kinase (AMPK). J. Biol. Chem. 290, 16979–16988 (2015).
Shin, A. C. et al. Insulin receptor signaling in POMC, but Not AgRP, neurons controls adipose tissue insulin action. Diabetes 66, 1560–1571 (2017).
Plum, L. et al. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J. Clin. Invest. 116, 1886–1901 (2006).
Choudhury, A. I. et al. The role of insulin receptor substrate 2 in hypothalamic and beta cell function. J. Clin. Invest. 115, 940–950 (2005).
Brito, M. N., Brito, N. A., Baro, D. J., Song, C. K. & Bartness, T. J. Differential activation of the sympathetic innervation of adipose tissues by melanocortin receptor stimulation. Endocrinology 148, 5339–5347 (2007).
Degerman, E. et al. in Diabetes Mellitus: A Fundamental and Clinical Text (eds LeRoith, D., Olefsky, J. M. & Taylor, S. I.) Ch. 24 374–381 (Lippincott Williams & Wilkins 2003).
Shrestha, Y. B. et al. Central melanocortin stimulation increases phosphorylated perilipin A and hormone-sensitive lipase in adipose tissues. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R140–R149 (2010).
Buettner, C. et al. Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat. Med. 14, 667–675 (2008).
Wang, J. et al. Overfeeding rapidly induces leptin and insulin resistance. Diabetes 50, 2786–2791 (2001).
Samuel, V. T. et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J. Biol. Chem. 279, 32345–32353 (2004).
Kraegen, E. W. et al. Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats. Diabetes 40, 1397–1403 (1991).
Tschritter, O. et al. The cerebrocortical response to hyperinsulinemia is reduced in overweight humans: a magnetoencephalographic study. Proc. Natl Acad. Sci. USA 103, 12103–12108 (2006).
Paolisso, G. et al. A high concentration of fasting plasma non-esterified fatty acids is a risk factor for the development of NIDDM. Diabetologia 38, 1213–1217 (1995).
Fabbrini, E. et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134, 424–431 (2008).
Smith, G. I. et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J. Clin. Invest. 130, 1453–1460 (2020).
Sparks, J. D. & Sparks, C. E. Insulin modulation of hepatic synthesis and secretion of apolipoprotein B by rat hepatocytes. J. Biol. Chem. 265, 8854–8862 (1990).
Malmstrom, R. et al. Metabolic basis of hypotriglyceridemic effects of insulin in normal men. Arterioscler. Thromb. Vasc. Biol. 17, 1454–1464 (1997).
Petersen, K. F. et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc. Natl Acad. Sci. USA 104, 12587–12594 (2007).
Gancheva, S. et al. Effects of intranasal insulin on hepatic fat accumulation and energy metabolism in humans. Diabetes 64, 1966–1975 (2015).
Stafford, J. M. et al. Central nervous system neuropeptide Y signaling modulates VLDL triglyceride secretion. Diabetes 57, 1482–1490 (2008).
Lam, T. K. et al. Brain glucose metabolism controls the hepatic secretion of triglyceride-rich lipoproteins. Nat. Med. 13, 171–180 (2007).
Yue, J. T. et al. A fatty acid-dependent hypothalamic-DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins. Nat. Commun. 6, 5970 (2015).
Hackl, M. T. et al. Brain leptin reduces liver lipids by increasing hepatic triglyceride secretion and lowering lipogenesis. Nat. Commun. 10, 2717 (2019).
Petersen, K. F. et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J. Clin. Invest. 109, 1345–1350 (2002).
Brown, R. J. et al. Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy. J. Clin. Invest. 128, 3504–3516 (2018).
Coomans, C. P. et al. Circulating insulin stimulates fatty acid retention in white adipose tissue via KATP channel activation in the central nervous system only in insulin-sensitive mice. J. Lipid Res. 52, 1712–1722 (2011).
Banks, W. A., Jaspan, J. B. & Kastin, A. J. Selective, physiological transport of insulin across the blood-brain barrier: novel demonstration by species-specific radioimmunoassays. Peptides 18, 1257–1262 (1997).
Wang, T. J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448–453 (2011).
Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).
Laferrere, B. et al. Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Sci. Transl Med. 3, 80re82 (2011).
She, P. et al. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am. J. Physiol. Endocrinol. Metab. 293, E1552–E1563 (2007).
Lanza, I. R. et al. Quantitative metabolomics by H-NMR and LC-MS/MS confirms altered metabolic pathways in diabetes. PLoS One 5, e10538 (2010).
Kim, J. Y. et al. Metabolic profiling of plasma in overweight/obese and lean men using ultra performance liquid chromatography and Q-TOF mass spectrometry (UPLC-Q-TOF MS). J. Proteome Res. 9, 4368–4375 (2010).
Mihalik, S. J. et al. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity 18, 1695–1700 (2010).
Harris, R. A., Joshi, M., Jeoung, N. H. & Obayashi, M. Overview of the molecular and biochemical basis of branched-chain amino acid catabolism. J. Nutr. 135, 1527S–1530S (2005).
Green, C. R. et al. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat. Chem. Biol. 12, 15–21 (2016).
Ruiz, H. H. et al. Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer’s disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels. Alzheimer Dement. 12, 851–861 (2016).
Scherer, T. et al. Chronic intranasal insulin does not affect hepatic lipids but lowers Circulating BCAAs in healthy male subjects. J. Clin. Endocrinol. Metab. 102, 1325–1332 (2017).
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
Muller, C. et al. Effect of chronic intracerebroventricular infusion of insulin on brown adipose tissue activity in fed and fasted rats. Int. J. Obes. Relat. Metab. Disord. 21, 562–566 (1997).
Bamshad, M., Song, C. K. & Bartness, T. J. CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am. J. Physiol. 276, R1569–R1578 (1999).
Sanchez-Alavez, M. et al. Insulin causes hyperthermia by direct inhibition of warm-sensitive neurons. Diabetes 59, 43–50 (2010).
Kleinridders, A., Ferris, H. A., Cai, W. & Kahn, C. R. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63, 2232–2243 (2014).
Sanchez-Alavez, M. et al. Insulin-like growth factor 1-mediated hyperthermia involves anterior hypothalamic insulin receptors. J. Biol. Chem. 286, 14983–14990 (2011).
Soto, M., Cai, W., Konishi, M. & Kahn, C. R. Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc. Natl Acad. Sci. USA 116, 6379–6384 (2019).
Benedict, C. et al. Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men. Diabetes 60, 114–118 (2011).
Ho, K. K. Y. Diet-induced thermogenesis: fake friend or foe? J. Endocrinol. 238, R185–R191 (2018).
Vitali, A. et al. The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes. J. Lipid Res. 53, 619–629 (2012).
Ikeda, K., Maretich, P. & Kajimura, S. The common and distinct features of brown and beige adipocytes. Trends Endocrinol. Metab. 29, 191–200 (2018).
Dodd, G. T. et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160, 88–104 (2015).
Dodd, G. T. et al. A hypothalamic phosphatase switch coordinates energy expenditure with feeding. Cell Metab. 26, 577 (2017).
Begg, D. P. & Woods, S. C. Interactions between the central nervous system and pancreatic islet secretions: a historical perspective. Adv. Physiol. Educ. 37, 53–60 (2013).
Chen, M., Woods, S. C. & Porte, D. Jr. Effect of cerebral intraventricular insulin on pancreatic insulin secretion in the dog. Diabetes 24, 910–914 (1975).
Woods, S. C. & Porte, D. Jr. Effect of intracisternal insulin on plasma glucose and insulin in the dog. Diabetes 24, 905–909 (1975).
Magnusson, I., Rothman, D. L., Katz, L. D., Shulman, R. G. & Shulman, G. I. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J. Clin. Invest. 90, 1323–1327 (1992).
Bruning, J. C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).
Buettner, C. et al. Severe impairment in liver insulin signaling fails to alter hepatic insulin action in conscious mice. J. Clin. Invest. 115, 1306–1313 (2005).
Titchenell, P. M., Chu, Q., Monks, B. R. & Birnbaum, M. J. Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo. Nat. Commun. 6, 7078 (2015).
O-Sullivan, I. et al. FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization. Nat. Commun. 6, 7079 (2015).
Ramnanan, C. J., Edgerton, D. S. & Cherrington, A. D. Evidence against a physiologic role for acute changes in CNS insulin action in the rapid regulation of hepatic glucose production. Cell Metab. 15, 656–664 (2012).
Edgerton, D. S. & Cherrington, A. D. Is brain insulin action relevant to the control of plasma glucose in humans? Diabetes 64, 696–699 (2015).
Lam, T. K., Gutierrez-Juarez, R., Pocai, A. & Rossetti, L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309, 943–947 (2005).
Lam, T. K. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat. Med. 11, 320–327 (2005).
Kishore, P. et al. Activation of K(ATP) channels suppresses glucose production in humans. J. Clin. Invest. 121, 4916–4920 (2011).
Pocai, A., Obici, S., Schwartz, G. J. & Rossetti, L. A brain-liver circuit regulates glucose homeostasis. Cell Metab. 1, 53–61 (2005).
Li, J. H. et al. Hepatic muscarinic acetylcholine receptors are not critically involved in maintaining glucose homeostasis in mice. Diabetes 58, 2776–2787 (2009).
Berthoud, H. R. & Neuhuber, W. L. Vagal mechanisms as neuromodulatory targets for the treatment of metabolic disease. Ann. NY Acad. Sci. 1454, 42–55 (2019).
Hill, J. W. et al. Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis. Endocrinology 150, 4874–4882 (2009).
Hill, J. W. et al. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 11, 286–297 (2010).
Konner, A. C. et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5, 438–449 (2007).
Lin, H. V. et al. Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. Diabetes 59, 337–346 (2010).
Lin, H. V. & Accili, D. Reconstitution of insulin action in muscle, white adipose tissue, and brain of insulin receptor knock-out mice fails to rescue diabetes. J. Biol. Chem. 286, 9797–9804 (2011).
Horwitz, D. L., Starr, J. I., Mako, M. E., Blackard, W. G. & Rubenstein, A. H. Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood. J. Clin. Invest. 55, 1278–1283 (1975).
Moore, M. C. et al. Effect of hepatic denervation on peripheral insulin sensitivity in conscious dogs. Am. J. Physiol. Endocrinol. Metab. 282, E286–E296 (2002).
Ramnanan, C. J., Edgerton, D. S., Kraft, G. & Cherrington, A. D. Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes. Metab. 13 (Suppl. 1), 118–125 (2011).
Moh, A. et al. STAT3 sensitizes insulin signaling by negatively regulating glycogen synthase kinase-3 beta. Diabetes 57, 1227–1235 (2008).
Chapman, C. D. et al. Intranasal treatment of central nervous system dysfunction in humans. Pharm. Res. 30, 2475–2484 (2013).
Dash, S., Xiao, C., Morgantini, C., Koulajian, K. & Lewis, G. F. Intranasal insulin suppresses endogenous glucose production in humans compared with placebo in the presence of similar venous insulin concentrations. Diabetes 64, 766–774 (2015).
Stengel, A. & Tache, Y. F. Activation of brain somatostatin signaling suppresses CRF receptor-mediated stress response. Front. Neurosci. 11, 231 (2017).
Heni, M. et al. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes 63, 4083–4088 (2014).
Waldhausl, W. K., Bratusch-Marrain, P. R., Francesconi, M., Nowotny, P. & Kiss, A. Insulin production rate in normal man as an estimate for calibration of continuous intravenous insulin infusion in insulin-dependent diabetic patients. Diabetes Care 5, 18–24 (1982).
Ott, V. et al. Central nervous insulin administration does not potentiate the acute glucoregulatory impact of concurrent mild hyperinsulinemia. Diabetes 64, 760–765 (2015).
Bohringer, A., Schwabe, L., Richter, S. & Schachinger, H. Intranasal insulin attenuates the hypothalamic-pituitary-adrenal axis response to psychosocial stress. Psychoneuroendocrinology 33, 1394–1400 (2008).
Born, J. et al. Sniffing neuropeptides: a transnasal approach to the human brain. Nat. Neurosci. 5, 514–516 (2002).
Jauch-Chara, K. et al. Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans. Diabetes 61, 2261–2268 (2012).
Krug, R., Benedict, C., Born, J. & Hallschmid, M. Comparable sensitivity of postmenopausal and young women to the effects of intranasal insulin on food intake and working memory. J. Clin. Endocrinol. Metab. 95, E468–E472 (2010).
Heni, M. et al. Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions. Diabetologia 55, 1773–1782 (2012).
Edgerton, D. S. et al. Changes in glucose and fat metabolism in response to the administration of a hepato-preferential insulin analog. Diabetes 63, 3946–3954 (2014).
Farmer, T. D. et al. Comparison of the physiological relevance of systemic vs. portal insulin delivery to evaluate whole body glucose flux during an insulin clamp. Am. J. Physiol. Endocrinol. Metab. 308, E206–E222 (2015).
Sindelar, D. K., Balcom, J. H., Chu, C. A., Neal, D. W. & Cherrington, A. D. A comparison of the effects of selective increases in peripheral or portal insulin on hepatic glucose production in the conscious dog. Diabetes 45, 1594–1604 (1996).
Luzi, L. et al. Metabolic effects of liver transplantation in cirrhotic patients. J. Clin. Invest. 99, 692–700 (1997).
Perseghin, G. et al. Regulation of glucose homeostasis in humans with denervated livers. J. Clin. Invest. 100, 931–941 (1997).
Schneiter, P. et al. Postprandial hepatic glycogen synthesis in liver transplant recipients. Transplantation 69, 978–981 (2000).
Gancheva, S. et al. Constant hepatic ATP concentrations during prolonged fasting and absence of effects of Cerbomed Nemos® on parasympathetic tone and hepatic energy metabolism. Mol. Metab. 7, 71–79 (2018).
Sathananthan, M. et al. The effect of vagal nerve blockade using electrical impulses on glucose metabolism in nondiabetic subjects. Diabetes Metab. Syndr. Obes. 7, 305–312 (2014).
Schmid, V. et al. Safety of intranasal human insulin: A review. Diabetes Obes. Metab. 20, 1563–1577 (2018).
Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl Med. 4, 147ra111 (2012).
Tonks, N. K. PTP1B: from the sidelines to the front lines! FEBS Lett. 546, 140–148 (2003).
Bence, K. K. et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat. Med. 12, 917–924 (2006).
Dodd, G. T. et al. Intranasal targeting of hypothalamic PTP1B and TCPTP reinstates leptin and insulin sensitivity and promotes weight loss in obesity. Cell Rep. 28, 2905–2922 (2019).
Moore, M. C. et al. Novel PEGylated basal insulin LY2605541 has a preferential hepatic effect on glucose metabolism. Diabetes 63, 494–504 (2014).
Henry, R. R. et al. Basal insulin peglispro demonstrates preferential hepatic versus peripheral action relative to insulin glargine in healthy subjects. Diabetes Care 37, 2609–2615 (2014).
Buse, J. B. et al. Randomized clinical trial comparing basal insulin peglispro and insulin glargine in patients with type 2 diabetes previously treated with basal insulin: IMAGINE 5. Diabetes Care 39, 92–100 (2016).
Grunberger, G. et al. A randomized clinical trial of basal insulin peglispro vs NPH in insulin-naive patients with type 2 diabetes: the IMAGINE 6 trial. Diabetes Obes. Metab. 18 (Suppl. 2), 34–42 (2016).
Begg, D. P. et al. Insulin detemir is transported from blood to cerebrospinal fluid and has prolonged central anorectic action relative to NPH insulin. Diabetes 64, 2457–2466 (2015).
Haak, T., Tiengo, A., Draeger, E., Suntum, M. & Waldhausl, W. Lower within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes. Diabetes Obes. Metab. 7, 56–64 (2005).
Dornhorst, A. et al. Transferring to insulin detemir from NPH insulin or insulin glargine in type 2 diabetes patients on basal-only therapy with oral antidiabetic drugs improves glycaemic control and reduces weight gain and risk of hypoglycaemia: 14-week follow-up data from PREDICTIVE. Diabetes Obes. Metab. 10, 75–81 (2008).
Hennige, A. M. et al. Tissue selectivity of insulin detemir action in vivo. Diabetologia 49, 1274–1282 (2006).
Hallschmid, M. et al. Euglycemic infusion of insulin detemir compared with human insulin appears to increase direct current brain potential response and reduces food intake while inducing similar systemic effects. Diabetes 59, 1101–1107 (2010).
Tschritter, O. et al. Cerebrocortical beta activity in overweight humans responds to insulin detemir. PLoS One 2, e1196 (2007).
Munoz-Garach, A., Molina-Vega, M. & Tinahones, F. J. How Can a Good Idea Fail? basal insulin peglispro [LY2605541] for the treatment of type 2 diabetes. Diabetes Ther. 8, 9–22 (2017).
Chen, J. E. & Glover, G. H. Functional magnetic resonance imaging methods. Neuropsychol. Rev. 25, 289–313 (2015).
Logothetis, N. K. What we can do and what we cannot do with fMRI. Nature 453, 869–878 (2008).
Heni, M. et al. Hypothalamic and striatal insulin action suppresses endogenous glucose production and may stimulate glucose uptake during hyperinsulinemia in lean but not in overweight men. Diabetes 66, 1797–1806 (2017).
Kullmann, S. et al. Dose-dependent effects of intranasal insulin on resting-state brain activity. J. Clin. Endocrinol. Metab. 103, 253–262 (2018).
Kullmann, S. et al. Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. Diabetes Care 38, 1044–1050 (2015).
Timper, K. & Bruning, J. C. Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity. Dis. Model. Mech. 10, 679–689 (2017).
Tiedemann, L. J. et al. Central insulin modulates food valuation via mesolimbic pathways. Nat. Commun. 8, 16052 (2017).
Edwin Thanarajah, S. et al. Modulation of midbrain neurocircuitry by intranasal insulin. Neuroimage 194, 120–127 (2019).
Novak, V. et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 37, 751–759 (2014).
Zhang, H. et al. Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes 64, 1025–1034 (2015).
Schilling, T. M. et al. Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation. Hum. Brain Mapp. 35, 1944–1956 (2014).
Kullmann, S. et al. Intranasal insulin modulates intrinsic reward and prefrontal circuitry of the human brain in lean women. Neuroendocrinology 97, 176–182 (2013).
Akintola, A. A. et al. Effect of intranasally administered insulin on cerebral blood flow and perfusion; a randomized experiment in young and older adults. Aging 9, 790–802 (2017).
Ketterer, C. et al. Polymorphism rs3123554 in CNR2 reveals gender-specific effects on body weight and affects loss of body weight and cerebral insulin action. Obesity 22, 925–931 (2014).
Guthoff, M. et al. The insulin-mediated modulation of visually evoked magnetic fields is reduced in obese subjects. PLoS One 6, e19482 (2011).
Stingl, K. T. et al. Insulin modulation of magnetoencephalographic resting state dynamics in lean and obese subjects. Front. Syst. Neurosci. 4, 157 (2010).
Tschritter, O. et al. High cerebral insulin sensitivity is associated with loss of body fat during lifestyle intervention. Diabetologia 55, 175–182 (2012).
Gross, J. Magnetoencephalography in cognitive neuroscience: a primer. Neuron 104, 189–204 (2019).
Pizzo, F. et al. Deep brain activities can be detected with magnetoencephalography. Nat. Commun. 10, 971 (2019).
Attal, Y. et al. Modeling and detecting deep brain activity with MEG & EEG. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2007, 4937–4940 (2007).
Hallschmid, M. et al. Transcortical direct current potential shift reflects immediate signaling of systemic insulin to the human brain. Diabetes 53, 2202–2208 (2004).
Kameyama, M., Murakami, K. & Jinzaki, M. Comparison of [(15)O] H2O positron emission tomography and functional magnetic resonance imaging in activation studies. World J. Nucl. Med. 15, 3–6 (2016).
Hirvonen, J. et al. Effects of insulin on brain glucose metabolism in impaired glucose tolerance. Diabetes 60, 443–447 (2011).
Colagiuri, S. & Brand Miller, J. The ‘carnivore connection’ — evolutionary aspects of insulin resistance. Eur. J. Clin. Nutr. 56 (Suppl. 1), S30–S35 (2002).
D’Costa, V. M. et al. Antibiotic resistance is ancient. Nature 477, 457–461 (2011).
D’Anastasio, R., Zipfel, B., Moggi-Cecchi, J., Stanyon, R. & Capasso, L. Possible brucellosis in an early hominin skeleton from sterkfontein, South Africa. PLoS One 4, e6439 (2009).
Rifkin, R. F., Potgieter, M., Ramond, J. B. & Cowan, D. A. Ancient oncogenesis, infection and human evolution. Evol. Appl. 10, 949–964 (2017).
Torsoni, M. A. et al. Molecular and functional resistance to insulin in hypothalamus of rats exposed to cold. Am. J. Physiol. Endocrinol. Metab. 285, E216–E223 (2003).
van der Crabben, S. N. et al. Prolonged fasting induces peripheral insulin resistance, which is not ameliorated by high-dose salicylate. J. Clin. Endocrinol. Metab. 93, 638–641 (2008).
Jais, A. & Bruning, J. C. Hypothalamic inflammation in obesity and metabolic disease. J. Clin. Invest. 127, 24–32 (2017).
Romanatto, T. et al. TNF-alpha acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient–effects on leptin and insulin signaling pathways. Peptides 28, 1050–1058 (2007).
Ramnanan, C. J. et al. Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs. J. Clin. Invest. 121, 3713–3723 (2011).
Honda, K., Kamisoyama, H., Saneyasu, T., Sugahara, K. & Hasegawa, S. Central administration of insulin suppresses food intake in chicks. Neurosci. Lett. 423, 153–157 (2007).
Brown, L. M., Clegg, D. J., Benoit, S. C. & Woods, S. C. Intraventricular insulin and leptin reduce food intake and body weight in C57BL/6J mice. Physiol. Behav. 89, 687–691 (2006).
Florant, G. L. et al. Intraventricular insulin reduces food intake and body weight of marmots during the summer feeding period. Physiol. Behav. 49, 335–338 (1991).
Clegg, D. J., Riedy, C. A., Smith, K. A., Benoit, S. C. & Woods, S. C. Differential sensitivity to central leptin and insulin in male and female rats. Diabetes 52, 682–687 (2003).
Woods, S. C. & Langhans, W. Inconsistencies in the assessment of food intake. Am. J. Physiol. Endocrinol. Metab. 303, E1408–E1418 (2012).
Hallschmid, M., Higgs, S., Thienel, M., Ott, V. & Lehnert, H. Postprandial administration of intranasal insulin intensifies satiety and reduces intake of palatable snacks in women. Diabetes 61, 782–789 (2012).
Plomgaard, P. et al. Nasal insulin administration does not affect hepatic glucose production at systemic fasting insulin levels. Diabetes Obes. Metab. 21, 993–1000 (2019).
Xiao, C., Dash, S., Stahel, P. & Lewis, G. F. Effects of intranasal insulin on triglyceride-rich lipoprotein particle production in healthy men. Arterioscler. Thromb. Vasc. Biol. 37, 1776–1781 (2017).
Fisher, S. J., Bruning, J. C., Lannon, S. & Kahn, C. R. Insulin signaling in the central nervous system is critical for the normal sympathoadrenal response to hypoglycemia. Diabetes 54, 1447–1451 (2005).
Kleinridders, A. et al. Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proc. Natl Acad. Sci. USA 112, 3463–3468 (2015).
Okamoto, H., Obici, S., Accili, D. & Rossetti, L. Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. J. Clin. Invest. 115, 1314–1322 (2005).
Klockener, T. et al. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat. Neurosci. 14, 911–918 (2011).
Grote, C. W. et al. Deletion of the insulin receptor in sensory neurons increases pancreatic insulin levels. Exp. Neurol. 305, 97–107 (2018).
Loh, K. et al. Insulin controls food intake and energy balance via NPY neurons. Mol. Metab. 6, 574–584 (2017).
Acknowledgements
The authors acknowledge the support of the Austrian Science Fund (FWF) grant KLI782 to T.S. and Manpei Suzuki Diabetes Foundation to K.S. and the NIH grants DK074873, DK083568 and DK082724 to C.B.
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Scherer, T., Sakamoto, K. & Buettner, C. Brain insulin signalling in metabolic homeostasis and disease. Nat Rev Endocrinol 17, 468–483 (2021). https://doi.org/10.1038/s41574-021-00498-x
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DOI: https://doi.org/10.1038/s41574-021-00498-x
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