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Start Over Author "Leibel, Rudolph L." Publisher american diabetes association
21 results on '"Leibel, Rudolph L."'

1. β-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome

Author

Shang, Linshan, Hua, Haiqing, Foo, Kylie, Martinez, Hector, Watanabe, Kazuhisa, Zimmer, Matthew, Kahler, David J., Freeby, Matthew, Chung, Wendy, LeDuc, Charles, Goland, Robin, Leibel, Rudolph L., and Egli, Dieter

Subjects
Ear diseases -- Physiological aspects, Cell research, Pancreatic beta cells -- Physiological aspects, Cellular control mechanisms -- Research, Health
Abstract

Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes. Diabetes 2014;63:923-933 | DOI: 10.2337/db13-0717, All forms of diabetes are ultimately the result of an inability of pancreatic β-cells to provide sufficient insulin in response to ambient blood glucose concentrations. Stem cell-based models of diabetes [...]

Published
2014
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2. Genetic studies of leptin concentrations implicate leptin in the regulation of early adiposity

Author

Admin, Ada, primary, Yaghootkar, Hanieh, primary, Zhang, Yiying, primary, Spracklen, Cassandra N, primary, Karaderi, Tugce, primary, Huang, Lam Opal, primary, Bradfield, Jonathan, primary, Schurmann, Claudia, primary, Fine, Rebecca S, primary, Preuss, Michael H, primary, Kutalik, Zoltan, primary, Wittemans, Laura BL, primary, Lu, Yingchang, primary, Metz, Sophia, primary, Willems, Sara M, primary, Li-Gao, Ruifang, primary, Grarup, Niels, primary, Wang, Shuai, primary, Molnos, Sophie, primary, Sandoval-Zárate, América A, primary, Nalls, Mike A, primary, Lange, Leslie A, primary, Haesser, Jeffrey, primary, Guo, Xiuqing, primary, Lyytikäinen, Leo-Pekka, primary, Feitosa, Mary F, primary, Sitlani, Colleen M, primary, Venturini, Cristina, primary, Mahajan, Anubha, primary, Kacprowski, Tim, primary, Wang, Carol A, primary, Chasman, Daniel I, primary, Amin, Najaf, primary, Broer, Linda, primary, Robertson, Neil, primary, Young, Kristin L, primary, Allison, Matthew, primary, Blüher, Matthias, primary, Borja, Judith B, primary, Bork-Jensen, Jette, primary, Carrasquilla, Germán D, primary, Christofidou, Paraskevi, primary, Demirkan, Ayse, primary, Doege, Claudia A, primary, Garcia, Melissa E, primary, Graff, Mariaelisa, primary, Guo, Kaiying, primary, Hakonarson, Hakon, primary, Hong, Jaeyoung, primary, Chen, Yii-Der Ida, primary, Jackson, Rebecca, primary, Jakupović, Hermina, primary, Jousilahti, Pekka, primary, Justice, Anne E, primary, Kähönen, Mika, primary, Kizer, Jorge R, primary, Kriebe, Jennifer, primary, LeDuc, Charles A, primary, Li, Jin, primary, Lind, Lars, primary, Luan, Jian’an, primary, Mackey, David, primary, Mangino, Massimo, primary, Männistö, Satu, primary, Carli, Jayne F Martin, primary, Medina-Gomez, Carolina, primary, Mook-Kanamori, Dennis O, primary, Morris, Andrew P, primary, Mutsert, Renée de, primary, Nauck, Matthias, primary, Nedeljkovic, Ivana, primary, Pennell, Craig E, primary, Pradhan, Arund D, primary, Psaty, Bruce M, primary, Raitakari, Olli T, primary, Scott, Robert A, primary, Skaaby, Tea, primary, Strauch, Konstantin, primary, Taylor, Kent D, primary, Teumer, Alexander, primary, Uitterlinden, Andre G, primary, Wu, Ying, primary, Yao, Jie, primary, Walker, Mark, primary, North, Kari E, primary, Kovacs, Peter, primary, Ikram, M. Arfan, primary, Duijn, Cornelia M van, primary, Ridker, Paul M, primary, Lye, Stephen, primary, Homuth, Georg, primary, Ingelsson, Erik, primary, Spector, Tim D, primary, McKnight, Barbara, primary, Province, Michael A, primary, Lehtimäki, Terho, primary, Adair, Linda S, primary, Rotter, Jerome I, primary, Reiner, Alexander P, primary, Wilson, James G, primary, Harris, Tamara B, primary, Ripatti, Samuli, primary, Grallert, Harald, primary, Meigs, James B, primary, Salomaa, Veikko, primary, Hansen, Torben, primary, Dijk, Ko Willems van, primary, Wareham, Nicholas J, primary, Grant, Struan FA, primary, Langenberg, Claudia, primary, Frayling, Timothy M, primary, Lindgren, Cecilia M, primary, Mohlke, Karen L, primary, Leibel, Rudolph L, primary, Loos, Ruth JF, primary, and Kilpeläinen, Tuomas O, primary

Published
2020
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3. Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity

Author

Yaghootkar, Hanieh, primary, Zhang, Yiying, additional, Spracklen, Cassandra N., additional, Karaderi, Tugce, additional, Huang, Lam Opal, additional, Bradfield, Jonathan, additional, Schurmann, Claudia, additional, Fine, Rebecca S., additional, Preuss, Michael H., additional, Kutalik, Zoltan, additional, Wittemans, Laura B.L., additional, Lu, Yingchang, additional, Metz, Sophia, additional, Willems, Sara M., additional, Li-Gao, Ruifang, additional, Grarup, Niels, additional, Wang, Shuai, additional, Molnos, Sophie, additional, Sandoval-Zárate, América A., additional, Nalls, Mike A., additional, Lange, Leslie A., additional, Haesser, Jeffrey, additional, Guo, Xiuqing, additional, Lyytikäinen, Leo-Pekka, additional, Feitosa, Mary F., additional, Sitlani, Colleen M., additional, Venturini, Cristina, additional, Mahajan, Anubha, additional, Kacprowski, Tim, additional, Wang, Carol A., additional, Chasman, Daniel I., additional, Amin, Najaf, additional, Broer, Linda, additional, Robertson, Neil, additional, Young, Kristin L., additional, Allison, Matthew, additional, Auer, Paul L., additional, Blüher, Matthias, additional, Borja, Judith B., additional, Bork-Jensen, Jette, additional, Carrasquilla, Germán D., additional, Christofidou, Paraskevi, additional, Demirkan, Ayse, additional, Doege, Claudia A., additional, Garcia, Melissa E., additional, Graff, Mariaelisa, additional, Guo, Kaiying, additional, Hakonarson, Hakon, additional, Hong, Jaeyoung, additional, Ida Chen, Yii-Der, additional, Jackson, Rebecca, additional, Jakupović, Hermina, additional, Jousilahti, Pekka, additional, Justice, Anne E., additional, Kähönen, Mika, additional, Kizer, Jorge R., additional, Kriebel, Jennifer, additional, LeDuc, Charles A., additional, Li, Jin, additional, Lind, Lars, additional, Luan, Jian’an, additional, Mackey, David A., additional, Mangino, Massimo, additional, Männistö, Satu, additional, Martin Carli, Jayne F., additional, Medina-Gomez, Carolina, additional, Mook-Kanamori, Dennis O., additional, Morris, Andrew P., additional, de Mutsert, Renée, additional, Nauck, Matthias, additional, Prokic, Ivana, additional, Pennell, Craig E., additional, Pradhan, Arund D., additional, Psaty, Bruce M., additional, Raitakari, Olli T., additional, Scott, Robert A., additional, Skaaby, Tea, additional, Strauch, Konstantin, additional, Taylor, Kent D., additional, Teumer, Alexander, additional, Uitterlinden, Andre G., additional, Wu, Ying, additional, Yao, Jie, additional, Walker, Mark, additional, North, Kari E., additional, Kovacs, Peter, additional, Ikram, M. Arfan, additional, van Duijn, Cornelia M., additional, Ridker, Paul M., additional, Lye, Stephen, additional, Homuth, Georg, additional, Ingelsson, Erik, additional, Spector, Tim D., additional, McKnight, Barbara, additional, Province, Michael A., additional, Lehtimäki, Terho, additional, Adair, Linda S., additional, Rotter, Jerome I., additional, Reiner, Alexander P., additional, Wilson, James G., additional, Harris, Tamara B., additional, Ripatti, Samuli, additional, Grallert, Harald, additional, Meigs, James B., additional, Salomaa, Veikko, additional, Hansen, Torben, additional, Willems van Dijk, Ko, additional, Wareham, Nicholas J., additional, Grant, Struan F.A., additional, Langenberg, Claudia, additional, Frayling, Timothy M., additional, Lindgren, Cecilia M., additional, Mohlke, Karen L., additional, Leibel, Rudolph L., additional, Loos, Ruth J.F., additional, and Kilpeläinen, Tuomas O., additional

Published
2020
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4. Waist circumference and cardiometabolic risk: a consensus statement from Shaping America's Health: Association for Weight Management and Obesity Prevention; NAASO, The Obesity Society; the American Society for Nutrition; and the American Diabetes Association

Author

Klein, Samuel, Allison, David B., Heymsfield, Steven B., Kelley, David E., Leibel, Rudolph L., Nonas, Cathy, and Kahn, Richard

Subjects
Obesity -- Complications and side effects -- Research -- Risk factors, Cardiovascular diseases -- Risk factors -- Research -- Complications and side effects, Health, Complications and side effects, Research, Risk factors
Abstract

Obesity is an important risk factor for cardiometabolic diseases, including diabetes, hypertension, dyslipidemia, and coronary heart disease (CHD). Several leading national and international institutions, including the World Health Organization (WHO) [...]

Published
2007

5. Is the energy homeostasis system inherently biased toward weight gain? (Perpectives In Diabetes)

Author

Schwartz, Michael W., Woods, Stephen C., Seeley, Randy J., Barsh, Gregory S., Baskin, Denis G., and Leibel, Rudolph L.

Subjects
Homeostasis -- Physiological aspects, Weight gain -- Risk factors, Weight gain -- Physiological aspects, Health
Abstract

We describe a model of energy homeostasis to better understand neuronal pathways that control energy balance and their regulation by hormonal signals such as insulin and leptin. Catabolic neuronal pathways are those that both reduce food intake and increase energy expenditure (e.g., melanocortin neurons in the hypothalamic arcuate nucleus) and are stimulated by input from insulin and leptin. We propose that in the basal state, catabolic effectors are activated in response to physiological concentrations of leptin and insulin, and that this activation is essential to prevent excessive weight gain. In contrast, anabolic pathways (e.g., neurons containing neuropeptide Y) are those that stimulate food intake and decrease energy expenditure and are strongly inhibited by these same basal concentrations of insulin and leptin. In the basal state, therefore, catabolic effector pathways are activated while anabolic effector pathways are largely inhibited. The response to weight loss includes both activation of anabolic and inhibition of catabolic pathways and is, thus, inherently more vigorous than the response to weight gain (stimulation of already-activated catabolic pathways and inhibition of already-suppressed anabolic pathways). Teleological, molecular, physiological, and clinical aspects of this hypothesis are presented, along with a discussion of currently available supporting evidence., Recent years have seen remarkable progress in understanding the genetic and molecular basis of body weight regulation. Key peripheral signals, such as leptin, have been linked to hypothalamic neuropeptide systems, [...]

Published
2003

6. Effects of leptin deficiency and short-term repletion on hepatic gene expression in genetically obese mice

Author

Ferrante, Jr., Anthony W., Thearle, Marie, Liao, Ted, and Leibel, Rudolph L.

Subjects
Obesity -- Physiological aspects -- Care and treatment, Diabetes -- Care and treatment, Leptin -- Physiological aspects, Health, Care and treatment, Physiological aspects
Abstract

By supplying most organs of the body with metabolic substrates, the liver plays a central role in maintaining energy balance. Hepatic metabolism of glucose, fatty acids, and lipoproteins is disrupted [...]

Published
2001

7. Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): evidence for deficient plasma-to-CSF transport of leptin in both the Zucker and Koletsky obese rat

Author

Wu-Peng, X. Sharon, Chua, Jr., Streamson C., Okada, Norichika, Liu, Shun-Mei, Nicoloson, Margery, and Leibel, Rudolph L.

Subjects
Diabetes -- Models -- Physiological aspects -- Analysis, Leptin -- Physiological aspects -- Models -- Analysis, Phenotype -- Analysis -- Physiological aspects -- Models, Health, Analysis, Physiological aspects, Models
Abstract

The obese phenotypes of the diabetes (db) mouse and fatty (fa) rat are due to functional null mutations of the leptin receptor (Lepr). The recessive mutation in the Koletsky (f) [...]

Published
1997

8. Absence of linkage of obesity and energy metabolism to markers flanking homologues of rodent obesity genes in Pima indians

Author

Norman, Rod A., Leibel, Rudolph L., Chung, Wendy K., Power-Kehoe, Loraine, Chua, Jr., Streamson C., Knowler, William C., Thompson, D. Bruce, Bogardus, Clifton, and Ravussin, Eric

Subjects
Obesity -- Genetic aspects, Bioenergetics -- Genetic aspects -- Health aspects, Pimas -- Health aspects, Energy metabolism -- Genetic aspects -- Health aspects, Genetics -- Health aspects -- Genetic aspects, Health, Genetic aspects, Health aspects
Abstract

The homologues of single genes that cause obesity in rodents are suggested as candidate genes for modulation of body composition in humans. Among these genes are the four mouse mutations-diabetes [...]

Published
1996

9. β-Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear Transfer Embryonic Stem Cells

Author

Sui, Lina, primary, Danzl, Nichole, additional, Campbell, Sean R., additional, Viola, Ryan, additional, Williams, Damian, additional, Xing, Yuan, additional, Wang, Yong, additional, Phillips, Neil, additional, Poffenberger, Greg, additional, Johannesson, Bjarki, additional, Oberholzer, Jose, additional, Powers, Alvin C., additional, Leibel, Rudolph L., additional, Chen, Xiaojuan, additional, Sykes, Megan, additional, and Egli, Dieter, additional

Published
2017
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10. The Gln223Arg and Lys656Asn polymorphisms in the human leptin receptor do not associate with traits related to obesity

Author

Silver, Kristi, Walston, Jeremy, Chung, Wendy K., Yao, Flora, Parikh, Vipul V., Andersen, Ross, Cheskin, Lawrence J., Elahi, Dariush, Muller, Denis, Leibel, Rudolph L., and Shuldiner, Alan R.

Subjects
Obesity -- Risk factors, Leptin -- Physiological aspects, Health, Physiological aspects, Risk factors
Abstract

The [Lepr.sup.db][Lepr.sup.db] mouse is an autosomal recessive model of extreme obesity that phenotypically appears very similar to the [Lepr.sup.db]/[Lepr.sup.db] mouse, in which the leptin protein is absent (1). However, in [...]

Published
1997

11. Exonic and intronic sequence variation in the human leptin receptor gene (LEPR)

Author

Chung, Wendy K., Power-Kehoe, Loraine, Chua, Melvin, Chu, Florence, Aronne, Louis, Huma, Zilla, Sothern, Melinda, Udall, John N., Kahle, Bowie, and Leibel, Rudolph L.

Subjects
Hormone receptors -- Genetic aspects, Leptin -- Genetic aspects, Health, Genetic aspects
Abstract

Increased adiposity is a major risk factor for cardiovascular disease and NIDDM[1]. Genetic determinants of the degree of adiposity and body fat distribution have been demonstrated by twin and adoption [...]

Published
1997

12. Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr)

Author

Chua, Jr., Streamson C., White, David W., Wu-Peng, X. Sharon, Liu, Shun-Mei, Okada, Norichika, Kershaw, Erin E., Chung, Wendy K., Power-Kehoe, Loraine, Chua, Melvin, Tartaglia, Louis A., and Leibel, Rudolph L.

Subjects
Obesity -- Genetic aspects, Diabetes -- Genetic aspects, Leptin -- Physiological aspects -- Genetic aspects, Genetics -- Physiological aspects -- Genetic aspects, Health, Physiological aspects, Genetic aspects
Abstract

The rat fatty (fa) mutation produces profound obesity of early onset caused by hyperphagia, defective nonshivering thermogenesis, and preferential deposition of energy into adipose tissue. Genetic mapping studies indicate that [...]

Published
1996

13. β-Cell Replacement in Mice Using Human Type 1 Diabetes Nuclear Transfer Embryonic Stem Cells.

Author

Sui, Lina, Danzl, Nichole, Campbell, Sean R., Viola, Ryan, Williams, Damian, Yuan Xing, Yong Wang, Phillips, Neil, Poffenberger, Greg, Johannesson, Bjarki, Oberholzer, Jose, Powers, Alvin C., Leibel, Rudolph L., Xiaojuan Chen, Sykes, Megan, Egli, Dieter, Xing, Yuan, Wang, Yong, and Chen, Xiaojuan

Subjects
TYPE 1 diabetes, TREATMENT of diabetes, LABORATORY mice, EMBRYONIC stem cells, STEM cell treatment, PATIENTS, PROTEIN metabolism, CELL differentiation, ANIMAL experimentation, BLOOD sugar, CELL lines, FLOW cytometry, GLUCOSE, IMMUNOHISTOCHEMISTRY, INSULIN, ISLANDS of Langerhans, MICE, RESEARCH funding, STEM cells, IMMUNOCOMPROMISED patients, PHYSIOLOGY
Abstract

β-Cells derived from stem cells hold great promise for cell replacement therapy for diabetes. Here we examine the ability of nuclear transfer embryonic stem cells (NT-ESs) derived from a patient with type 1 diabetes to differentiate into β-cells and provide a source of autologous islets for cell replacement. NT-ESs differentiate in vitro with an average efficiency of 55% into C-peptide-positive cells, expressing markers of mature β-cells, including MAFA and NKX6.1. Upon transplantation in immunodeficient mice, grafted cells form vascularized islet-like structures containing MAFA/C-peptide-positive cells. These β-cells adapt insulin secretion to ambient metabolite status and show normal insulin processing. Importantly, NT-ES-β-cells maintain normal blood glucose levels after ablation of the mouse endogenous β-cells. Cystic structures, but no teratomas, were observed in NT-ES-β-cell grafts. Isogenic induced pluripotent stem cell lines showed greater variability in β-cell differentiation. Even though different methods of somatic cell reprogramming result in stem cell lines that are molecularly indistinguishable, full differentiation competence is more common in ES cell lines than in induced pluripotent stem cell lines. These results demonstrate the suitability of NT-ES-β-cells for cell replacement for type 1 diabetes and provide proof of principle for therapeutic cloning combined with cell therapy. [ABSTRACT FROM AUTHOR]

Published
2018
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14. Transgenic Complementation of Leptin-Receptor Deficiency

Author

Kowalski, Timothy J., Liu, Shun-Mei, Leibel, Rudolph L., and Chua, Streamson C. Jr.

Subjects
Obesity -- Health aspects -- Research, Diabetes -- Research, Leptin -- Physiological aspects -- Health aspects -- Research, Health, Physiological aspects, Research, Health aspects
Abstract

I. Rescue of the Obesity/Diabetes Phenotype of LEPR-Null Mice Expressing a LEPR-B Transgene Mice homozygous for the [Lepr.sup.db3J] ([db.sup.3J]) mutation are null for all known isoforms of the leptin receptor [...]

Published
2001

16. Genetic and Physiologic Analysis of the Role of Uncoupling Protein 3 in Human Energy Homeostasis

Author

Chung, Wendy K., Luke, Amy, Cooper, Richard S., Rotini, Charles, Vidal-Puig, Antonio, Rosenbaum, Michael, Chua, Melvin, Solanes, Gemma, Zheng, Min, Zhao, Long, LeDuc, Charles, Eisberg, Andrew, Chu, Florence, Murphy, Ellen, Schreier, Mindy, Aronne, Louis, Caprio, Sonia, Kahle, Bowie, Gordon, Derek, Leal, Suzanne M., Goldsmith, Rochelle, Andreu, Antonio L., Bruno, Claudio, DiMauro, Salvatore, Heo, Moonseong, Lowe, William L. Jr., Lowell, Bradford B., Allison, David B., and Leibel, Rudolph L.

Subjects
Obesity -- Genetic aspects, Homeostasis -- Physiological aspects -- Genetic aspects, Genetics -- Physiological aspects -- Genetic aspects, Health, Physiological aspects, Genetic aspects
Abstract

By virtue of its potential effects on rates of energy expenditure, uncoupling protein 3 (UCP3) is an obesity candidate gene. We identified nine sequence variants in UCP3, including Val9Met, Vall0211e, [...]

Published
1999

17. Clinical Characteristics In An Ethnically Diverse Group Of Children With Type 2 Diabetes

Author

VARGAS, ILEANA, SCHACHNER, HOLLY C., SOLOWIEJCZYK, JOE, ALMEIDA, KIRA L., LEIBEL, RUDOLPH L., and GOLAND, ROBIN S.

Subjects
Diabetes -- Research, Health
Abstract

Although generally considered a disease of adulthood, type 2 diabetes is increasingly being seen in children and adolescents. We report the clinical characteristics of 19 children (9 boys, 10 girls) [...]

Published
1999

18. An apparent role for Alox15 in the pathogenesis of diabetes in the NOD mouse: parsing the supporting genetic data

Author

Weisberg, Stuart P. and Leibel, Rudolph L.

Subjects
Type 1 diabetes -- Genetic aspects -- Research -- Development and progression, Health, Development and progression, Research, Genetic aspects
Abstract

Progenitors of the nonobese diabetic mouse strain arose spontaneously in a colony at the Shionogi Research Laboratories in Aburahi, Japan in the 1970s. The strain has been used extensively in [...]

Published
2008

19. β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome.

Author

Linshan Shang, Haiqing Hua, Kylie Foo, Martinez, Hector, Kazuhisa Watanabe, Zimmer, Matthew, Kahler, David J., Freeby, Matthew, Chung, Wendy, LeDuc, Charles, Goland, Robin, Leibel, Rudolph L., and Egli, Dieter

Subjects
WOLFRAM syndrome, ENDOCRINE diseases, DIABETES, ENDOPLASMIC reticulum, INSULIN synthesis, STEM cell research
Abstract

Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes. [ABSTRACT FROM AUTHOR]

Published
2014
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21. Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity

Author

Yaghootkar, Hanieh, Zhang, Yiying, Spracklen, Cassandra N, Karaderi, Tugce, Huang, Lam Opal, Bradfield, Jonathan, Schurmann, Claudia, Fine, Rebecca S, Preuss, Michael H, Kutalik, Zoltan, Wittemans, Laura BL, Lu, Yingchang, Metz, Sophia, Willems, Sara M, Li-Gao, Ruifang, Grarup, Niels, Wang, Shuai, Molnos, Sophie, Sandoval-Zárate, América A, Nalls, Mike A, Lange, Leslie A, Haesser, Jeffrey, Guo, Xiuqing, Lyytikäinen, Leo-Pekka, Feitosa, Mary F, Sitlani, Colleen M, Venturini, Cristina, Mahajan, Anubha, Kacprowski, Tim, Wang, Carol A, Chasman, Daniel I, Amin, Najaf, Broer, Linda, Robertson, Neil, Young, Kristin L, Allison, Matthew, Auer, Paul L, Blüher, Matthias, Borja, Judith B, Bork-Jensen, Jette, Carrasquilla, Germán D, Christofidou, Paraskevi, Demirkan, Ayse, Doege, Claudia A, Garcia, Melissa E, Graff, Mariaelisa, Guo, Kaiying, Hakonarson, Hakon, Hong, Jaeyoung, Ida Chen, Yii-Der, Jackson, Rebecca, Jakupović, Hermina, Jousilahti, Pekka, Justice, Anne E, Kähönen, Mika, Kizer, Jorge R, Kriebel, Jennifer, LeDuc, Charles A, Li, Jin, Lind, Lars, Luan, Jian'an, Mackey, David A, Mangino, Massimo, Männistö, Satu, Martin Carli, Jayne F, Medina-Gomez, Carolina, Mook-Kanamori, Dennis O, Morris, Andrew P, De Mutsert, Renée, Nauck, Matthias, Prokic, Ivana, Pennell, Craig E, Pradhan, Arund D, Psaty, Bruce M, Raitakari, Olli T, Scott, Robert A, Skaaby, Tea, Strauch, Konstantin, Taylor, Kent D, Teumer, Alexander, Uitterlinden, Andre G, Wu, Ying, Yao, Jie, Walker, Mark, North, Kari E, Kovacs, Peter, Ikram, M Arfan, Van Duijn, Cornelia M, Ridker, Paul M, Lye, Stephen, Homuth, Georg, Ingelsson, Erik, Spector, Tim D, McKnight, Barbara, Province, Michael A, Lehtimäki, Terho, Adair, Linda S, Rotter, Jerome I, Reiner, Alexander P, Wilson, James G, Harris, Tamara B, Ripatti, Samuli, Grallert, Harald, Meigs, James B, Salomaa, Veikko, Hansen, Torben, Willems Van Dijk, Ko, Wareham, Nicholas J, Grant, Struan FA, Langenberg, Claudia, Frayling, Timothy M, Lindgren, Cecilia M, Mohlke, Karen L, Leibel, Rudolph L, Loos, Ruth JF, and Kilpeläinen, Tuomas O

Subjects
2. Zero hunger, Leptin, Models, Molecular, Genotype, Protein Conformation, digestive, oral, and skin physiology, Racial Groups, Gene Expression Regulation, Developmental, Genetic Variation, Humans, hormones, hormone substitutes, and hormone antagonists, Adiposity
Abstract

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

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