PerspectiveBiomedicine

Staying Slim with Insulin in Mind

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Science  22 Sep 2000:
Vol. 289, Issue 5487, pp. 2066-2067
DOI: 10.1126/science.289.5487.2066

When Banting and Best first administered insulin [HN1] to patients with uncontrolled diabetes [HN2], they established its crucial importance in the regulation of blood glucose concentration. Secreted by the b-islet cells of the endocrine pancreas, insulin [HN3] exerts its glucose-lowering effects by stimulating glucose uptake in tissues such as skeletal muscle, suppressing fatty acid release from adipose (fat) tissue, and inhibiting production of glucose by the liver (see the figure). Muscle, liver, and fat, therefore, are widely viewed as the principal “insulin-sensitive” tissues in the body. The brain, in contrast, has historically been considered “insulin-insensitive” because its ability to use glucose does not require insulin. Therefore, the notion that insulin participates in the central nervous system (CNS) control of food intake and body weight was received with a good deal of skepticism when it was first proposed by Woods and Porte [HN4] more than 20 years ago (1). Since then, however, support for this hypothesis has steadily accumulated, including the demonstration that insulin is transported across the blood-brain barrier [HN5], that it is effective in suppressing food intake when given directly into the brain, and that insulin receptors [HN6] are concentrated in brain areas involved in energy homeostasis (2). Now, Brüning and colleagues [HN7] (3) provide important evidence to support this hypothesis with their report on page 2122 of this issue. They show that mice lacking insulin receptors in the brain have an increased body fat content (adiposity), demonstrating that insulin signaling [HN8] in the brain is essential for normal regulation of adiposity.

Insulin weighs in.

Insulin regulates blood glucose and body adiposity. (Left) Insulin lowers blood glucose concentration by suppressing its production by the liver and promoting its uptake into “insulin-sensitive” tissues such as muscle and fat. Insulin also crosses the blood-brain barrier to enter the CNS, where it reduces food intake and consequently reduces absorption of glucose and other nutrients into the body. (Right) Glucose-induced insulin secretion from the pancreas increases in proportion to body adiposity, owing to the capability of expanding fat stores to induce resistance to insulin's glucose-lowering effects.

The hypothesis that body fat stores are subject to negative-feedback regulation was formally introduced by Kennedy in 1953 (4). He proposed that humoral signals, generated in proportion to body fat stores, act in the brain to lower food intake and body weight [HN9]. Hence, weight loss induced, for example, by restricting food intake was suggested to decrease circulating “adiposity signals” and thereby to increase the drive to eat until the deficit in body adiposity is corrected. To qualify as an adiposity signal, candidate molecules should circulate and traverse the blood-brain barrier at levels proportionate to body fat content. Within the brain, they should influence the activity of key neurons to promote anorexia and weight loss, and a deficiency of such signals should stimulate feeding behavior. Insulin was the only known molecule to meet these criteria until the discovery in 1994 of leptin [HN10] (5), a hormone secreted by fat cells (adipocytes) that also circulates at levels proportionate to fat stores and acts in the brain to reduce food intake and body weight.

Several observations seem to contradict the notion of insulin as a physiological signal to the brain that promotes weight loss. For one, insulin deficiency in type 1 diabetes [HN11] does not cause weight gain, but rather is associated with severe, progressive weight loss. This apparent paradox is reconciled by recognizing that in addition to its effects on blood glucose and food intake, insulin is a potent stimulus for the synthesis and storage of fat. Thus, untreated insulin-deficient type 1 diabetes is characterized by the expected increases in blood glucose (hyperglycemia) and food intake (hyperphagia), but ingested calories are not stored as fat and instead are expended or lost in the urine. Therefore, severe insulin deficiency does not coexist with weight gain, as insulin is required to maintain and increase energy storage in the body. This situation contrasts sharply with the severe obesity syndrome that accompanies leptin deficiency (5).

Whereas leptin deficiency and insulin deficiency have opposing effects on body weight, their effects on food intake and hypothalamic function [HN12] are similar. Hyperphagia occurs in both conditions and is associated with increased hypothalamic signaling by orexigenic (appetite-stimulating) peptides such as neuropeptide Y (NPY) and agouti-related peptide [HN13] (AgRP), and decreased signaling from anorexigenic peptides such as melanocortins (6). Despite pronounced differences in body fat storage, therefore, the consequences of reduced CNS signaling by leptin and insulin parallel one another closely.

Thus, insulin enhances fat storage through stimulation of the adipocyte, while promoting weight loss through leptin-like actions in the brain. One way to investigate the specific contribution of brain insulin signaling to the control of body adiposity is to delete insulin receptors in the brain using Cre-loxP genetic engineering technology [HN14] (7). The hypothesis that insulin is an adiposity signal to the CNS predicts that a selective loss of neuronal insulin receptors should induce excessive fat storage. The finding by Brüning and co-workers (3) that mice with a neuron-specific deficiency in insulin receptors (NIRKO mice) have increased body fat content and are predisposed to the obesity-promoting effects of a high-fat diet provides direct support for this hypothesis. As these responses are mediated only in part by increased food intake (detected in female but not male mice consuming a regular chow diet), brain insulin signaling appears to be essential for normal control of both energy intake and energy expenditure.

The energy-deprived state activates a host of adaptive neuroendocrine responses in addition to a heightened drive to eat, and reduced signaling by insulin and leptin is implicated in these responses as well. For example, starvation acutely suppresses reproductive function by inhibiting hypothalamic neurons that drive the pulsatile release of pituitary gonadotrophins. Because leptin administration partially restores reproductive capabilities to fasted mice (8), leptin deficiency is implicated in this response [HN15]. The restorative effect of leptin was incomplete, however, suggesting that other factors help to mediate the inhibitory effects of food deprivation on the reproductive axis. The finding that NIRKO mice have a similar hypothalamic impairment of reproduction (3) suggests that reduced neuronal signaling by both insulin and leptin is involved in this adaptive response to starvation. Although levels of gonadal steroids were not reported, deficiency of these hormones is a likely concomitant of the reproductive deficit in NIRKO mice, and this in and of itself can cause weight gain. The extent to which obesity in these animals is the product of hypogonadism, rather than being a direct consequence of reduced insulin signaling in the brain, is a question that requires further study.

The pervasive notion that insulin causes obesity, like the tenet that the brain is insulin-insensitive, has hindered acceptance of insulin as a signal to the brain that limits weight gain. Although the concept that insulin triggers weight gain has little scientific merit, it remains a key selling point for advocates of diets that are low in carbohydrate and high in protein and fat. It is true that obesity is strongly associated with increased circulating insulin levels (hyperinsulinemia) [HN16], but this relation is most likely due to obesity-induced insulin resistance, rather than to obesity-promoting effects of insulin, because increased insulin secretion actually protects against subsequent weight gain in obese humans (9). If hyperinsulinemia has adverse consequences, obesity does not appear to be among them.

Although leptin appears to play a quantitatively more important part than insulin in the CNS control of energy homeostasis, the phenotype of mice lacking neuronal insulin receptors indicates that brain insulin signaling is involved. Recent studies demonstrate that obesity induced by a high-fat diet causes hypothalamic resistance to leptin (10) and impairs insulin transport into the brain (11). Combined with evidence that leptin and insulin can influence glucose homeostasis through actions at a central site (3, 12), the stage is now set for studies to determine if impaired CNS signaling by insulin and leptin contribute to the pathogenesis of two common metabolic diseases, obesity [HN17] and type 2 diabetes [HN18].

HyperNotes Related Resources on the World Wide Web

General Hypernotes

The On-line Medical Dictionary is provided by CancerWeb.

Biology Links are provided by the Department of Molecular and Cellular Biology, Harvard University.

HealthWeb, a collaborative project of health sciences libraries, offers annotated listings of evaluated Internet resources.

Cell & Molecular Biology Online, maintained by P. Gannon, is a collection of annotated links to Internet resources

The library of the Karolinska Institutet, Stockholm, provides links to biomedical information resources and services on the Internet. A section on diabetes and other endocrine diseases is included.

The CMS Molecular Biology Resource is a compendium of electronic and Internet-accessible tools and resources for molecular biology, biotechnology, molecular evolution, biochemistry, and biomolecular modeling.

Links of Interest in Endocrinology are provided by the Illinois State Academy of Science.

Britannica.com offers an Encyclopædia Britannicaarticle about endocrinology and the human endocrine system.

The Online Biology Book by M. Farabee, Estrella Mountain Community College, Avondale, AZ, includes presentations on the endocrine system and on the nervous system.

P.-E. Paulev, Department of Medical Physiology, University of Copenhagen, makes available on the Web his textbookMedical Physiology and Pathophysiology. A chapter on diabetes is included.

R. Gore, Department of Physiology, University of Arizona, provides a series of lecture notes on the endocrine system for a human physiology course.

R. Vogt, Department of Biological Sciences, University of South Carolina, offers lecture notes on the endocrine system for a biology course.

LectureLinks from the Johns Hopkins School of Medicine offers a collection of endocrinology lecture notes.

Pathophysiology of the Endocrine System is a Web hypertextbook presented by R. Bowen, Animal Reproduction and Biotechnology Laboratory, Colorado State University.

The April 1999 issue of the American Journal of Clinical Nutrition had an article by M. Schwartz et al. titled “Model for the regulation of energy balance and adiposity by the central nervous system.”

Numbered Hypernotes

1. The Banting and Best Department of Medical Research, University of Toronto, offers a presentation on the discovery of insulin. The Nobel Prize in Physiology or Medicine 1923 was presented to Frederick Grant Banting and John James Richard Macleod “for the discovery of insulin.” The chapter on the history of diabetes from the International Textbook of Diabetes Mellitus is made available by Wiley's Diabetes Website. The Discovery of Insulin is a Web exhibit sponsored by the Sir Frederick Banting Educational Committee, New Tecumseth, ON, Canada.

2. Health Oasis from the Mayo Clinic provides an introduction to diabetes. Britannica.com offers an Encyclopædia Britannica article on diabetes. The chapter on diabetes from Harrison's Online is made available by the publisher McGraw-Hill. T. Fekete, Section of Infectious Diseases, Temple University School of Medicine, provides an overview of diabetes mellitus in a collection of pathophysiology course resources. The Merck Manual of Diagnosis and Therapy, made available on the Web by Merck & Co, Inc., includes a section on diabetes; the Merck Manual of Medical Information—Home Edition provides information about diabetes in less technical language. The American Diabetes Association provides diabetes information and news. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provides information resources related to diabetes. The Joslin Diabetes Center, Harvard Medical School, provides an online diabetes library. On-line Diabetes Resources is an annotated list of Internet resources maintained by R. Mendosa. The April 1997 issue of Postgraduate Medicine had an article by J. MacCracken titled “From ants to analogues: Puzzles and promises in diabetes management” about the history of diabetes and its treatment.

3. The Encyclopædia Britannica article on hormones has a section on insulin. The National Institute for Medical Research, London, makes available an essay by G. Dodson titled “Insulin and diabetes.” Kimball's Biology Pages provide an introduction to insulin and other pancreatic hormones. Endocrine Web provides a diabetes information center that includes an introduction to insulin, as well as an overview of the endocrine pancreas. Pathophysiology of the Endocrine System includes a chapter on the endocrine pancreas with sections on insulin synthesis and secretion and the physiologic effects of insulin. An introduction to insulin is included in the overview chapter on diabetes in the Healing Handbook for Persons with Diabetes, a Web book provided by the University of Massachusetts. T. Dorsch's Diabetes Central offers presentations on insulin and insulin resistance. LectureLinks from the Johns Hopkins School of Medicine offers lecture notes by D. Raben on insulin and glycogen. “Structure/function relationship of insulin and related hormones” is a student Web project by Y.-Y. Cheng, prepared for a course on biophysical chemistry taught by S. Hartsel, Department of Chemistry, University of Wisconsin, Eau Claire.

4. S. Woods is at the Obesity Research Center, Department of Psychiatry, University of Cincinnati College of Medicine. D. Porte is in the Division of Metabolism, Endocrinology and Nutrition, University of Washington School of Medicine, and at the Diabetes Endocrinology Research Center, VA Puget Sound Health Care System.

5. E. Chudler's Neuroscience for Kids offers a presentation on the blood-brain barrier. The Blood-Brain Barrier Homepage from the UCLA School of Medicine provides an introduction to the blood-brain barrier. The JAMA HIV/AIDS Information Center offers a background briefing on the blood-brain barrier. The Society for Neuroscience provides a briefing about the blood-brain barrier; a briefing titled “Insulin, the brain and memory” is also available.

6. J. Brown, Department of Molecular Biosciences, University of Kansas, provides an introduction to receptors. Online Mendelian Inheritance in Man (OMIM) has an entry for insulin receptor.

7. J. Brüning, W. Krone, and D. Müller-Wielandare are at the Klinik II und Poliklinik für Innere Medizin and the Zentrum für Molekulare Medizin, Universität Köln, Germany. C. Kahn is at the Joslin Diabetes Center, Harvard Medical School. R. Klein is at the European Molecular Biology Laboratory, Heidelberg, Germany.

8. T. Terry, Department of Molecular and Cell Biology, University of Connecticut, provides lecture notes on cell signaling for a biology course. For a course on molecular and cell biology, the Molecular Biology Program, New Mexico State University, provides lecture notes on cell signaling. The June 2000 issue of Scientific American had an article by J. Scott and T. Pawson about signaling titled “Cell communication: The inside story.”

9. E. Corp, Neuroscience and Behavior Graduate Program, University of Massachusetts, mentions G. C. Kennedy's theory in lecture notes titled “Theories of hunger: The CNS neural targets of feeding signals” for a psychology course on motivation and emotion. Lecture notes by Z. Gottesfeld on the central control of food intake are included in the unit on homeostasis and higher brain function of a neuroscience course offered by the Department of Neurobiology and Anatomy, University of Texas Houston Medical School; a discussion of neuropeptides and the control of food intake is included. The 29 May 1998 issue of Science had an article by S. Woods et al. titled “Signals that regulate food intake and energy homeostasis.”

10. Rockefeller University issued new releases on 27 July 1995 and 31 October 1995 about the leptin research of J. Friedman and colleagues. The Howard Hughes Medical Institute provides information about Friedman's research. Kimball's Biology Pages offers an introduction to leptin. Pathophysiology of the Endocrine System offers a presentation on leptin. The May 1998 issue of the Journal of Clinical Endocrinology & Metabolism had an article by J. Flier titled “What's in a name? In Search of leptin's physiologic role.” OMIM has an entry for leptin and leptin receptor. The GeneCards database from the Weizmann Institute has an entry for LEPR (leptin receptor). The April 1999 issue of Physiological Reviews had an article by E. Jéquier and L. Tappy titled “Regulation of body weight in humans”; a section on the role of leptin is included. The June 1998 issue of the Brazilian Journal of Medical and Biological Research had an article by R. Ceddia et al. titled “Pivotal role of leptin in insulin effects.”

11. The THCME Medical Biochemistry Pages maintained by M. King, Terre Haute Center for Medical Education, IN, provide an introduction to type 1 diabetes. The eMedicine.com Web site offers a review of diabetes mellitus, type 1 by S. Votey and A. Peters. Type 1 Diabetes: Molecular, Cellular, and Clinical Immunology is a book edited by G. Eisenbarth and K. Lafferty made available on the Web by the Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center. Genes and Disease, a Web presentation by the National Center for Biotechnology Information (NCBI), includes a section on type 1 diabetes.

12. Britannica.com offers an Encyclopædia Britannica article on the hypothalamus. The Neuroscience Tutorial from the Washington University School of Medicine includes a presentation on the hypothalamus. The University of Massachusetts Medical School provides lecture notes on the hypothalamus for a course on mind, brain, and behavior. The February 1997 issue of the Proceedings of the National Academy of Sciences had an article by W. Yu et al. titled “Role of leptin in hypothalamic-pituitary function.”

13. Pathophysiology of the Endocrine System includes sections on neuropeptide Y and melanocortins and the melanocortin receptor. The Web edition of Psychopharmacology, The Fourth Generation of Progress, provided by the American College of Neuropsychopharmacology, includes a chapter by C. Wahlestedt and M. Heilig titled “Neuropeptide Y and related peptides”; a chapter by T. Hökfelt et al. titled “General overview of neuropeptides” is also included. Phoenix Pharmaceuticals, Inc., provides information about neuropeptide Y and AgRP. OMIM provides information about NPY, AgRP, and melanocortins. The GeneCards database includes entries for NPY and AgRP. The Howard Hughes Medical Institute provides a research profile of G. Barsh titled “Developmental genetics of mouse coat color and obesity.”

14. The Van Duyne Research Group, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, offers information about the Cre-loxP system. U. Wagner, Laboratory of Genetics and Physiology, NIDDK, provides a presentation titled “The Cre/loxP recombination system in transgenic mice.” R. Feil, Institut für Pharmakologie und Toxikologie, Technische Universität München, Germany, provides an introduction to the Cre-loxP system in a presentation titled “Conditional gene targeting in the mouse.”

15. The February 1999 issue of Biology of Reproduction had an article by M. Cunningham, D. Clifton, and R. Steiner titled “Leptin's actions on the reproductive axis: Perspectives and Mechanisms.”

16. A presentation on hyperinsulinemia is provided by eMedicine.com. The WorldMedicus Web site provides links to information about hyperinsulinemia.

17. NCBI's Genes and Disease Web exhibit includes a presentation on obesity. About Obesity is an Internet resource for the public and professionals provided by the Donald B. Brown Research Chair on Obesity, Laval University, Quebec. The North American Association for the Study of Obesity makes available the contents of its journal Obesity Research on the Web and provides a collection of links to obesity-related Internet resources. The Society for Neuroscience offers a briefing on weight control and obesity. The March 1998 issue of Hospital Practice had an article by J. Hirsch and R. Leibel titled “The genetics of obesity.” The Web edition of Psychopharmacology, The Fourth Generation of Progress includes a chapter by M. Bray titled “Obesity, fat intake and chronic disease.” NIDDK offers a presentation on understanding adult obesity. The August 1996 issue of Scientific American had an article by W. W. Gibbs titled “Gaining on fat.” J. Hirsch's Laboratory of Human Behavior and Metabolism at Rockefeller University offers apresentation on its research on the molecular genetics of obesity/diabetes.

18. The THCME Medical Biochemistry Pages provide an introduction to type 2 diabetes. A review of diabetes mellitus, type 2 by S. Votey and A. Peters is available from eMedicine.com.

19. M. Schwartz is in the Division of Metabolism, Endocrinology and Nutrition, University of Washington.

References and Notes

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