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Neuroendocrine Regulation of Metabolism and Neurocognition
- Joan C. Han, MD, Head, Unit on Metabolism and Neuroendocrinology
- Alyson E. Spore, MSN, RN, Predoctoral Fellow
- Melanie D. Hicks, BA, Postbaccalaureate Fellow
- Amanda E. Huey, BA, Postbaccalaureate Fellow
- Seo Yoon Chung, Special Volunteer
- Lindsay A. Hunter, BA, Special Volunteer
- Mark D. Lee, Special Volunteer
- Zongyang Mou, Special Volunteer
- Gladys I. Palaguachi, BA, Special Volunteer
- Dmytro Mikhnev, Special Volunteer
- Tanvee Singh, Special Volunteer
- Matthew M. Tsang, Special Volunteer
- Emily G. Yin, Special Volunteer
- Katrina L. Epperson, BA, Summer Intern
The goal of our translational research is to gain insight into the neuroendocrine regulation of human energy homeostasis and cognitive function. We conduct clinical studies on healthy subjects as well as on patients with rare genetic disorders associated with childhood obesity and intellectual, psychiatric, and/or behavioral abnormalities. Our laboratory studies aim to elucidate mechanisms within the central nervous system that control both metabolism and neurodevelopment. We hope that a better understanding of the pathophysiology of energy imbalance and cognitive impairment will lead to therapies for improving body composition and neurocognition.
Genotype-phenotype correlation studies in WAGR/11p deletion syndrome
We have been conducting a comprehensive genotype-phenotype correlation study in patients with WAGR (Wilms tumor, aniridia, genitourinary anomalies, mental retardation) syndrome, which is caused by heterozygous contiguous gene deletions of variable size in the chromosome 11p13 region. We previously observed that haploinsufficiency for BDNF, the gene that encodes brain-derived neurotrophic factor (BDNF), is associated with elevated prevalence of childhood obesity and elevated scores on a hyperphagia questionnaire. BDNF is widely expressed throughout the nervous system and plays an important role in neuronal development and synaptic plasticity. In animal studies, BDNF appears to function downstream of the leptin signaling pathway to regulate appetite and energy balance. Our findings support the role of BDNF in human energy homeostasis. We have been conducting further studies to characterize the role of BDNF in neurocognitive function because Bdnf+/− mice are not only hyperphagic and obese but also exhibit learning deficits, behavioral abnormalities, and decreased thermal pain response. In a cohort of 31 patients with WAGR syndrome, we observed that BDNF haploinsufficiency is associated with significantly reduced scores on a parent-completed questionnaire assessing behavior responses to injuries or illnesses considered painful to most people. The findings suggest that BDNF plays a role in human nociception. Studies are currently under way to examine detection and pain thresholds for hot and cold stimuli. Tests of cognitive and adaptive function, psychiatric symptoms, and autism spectrum diagnoses are also ongoing. In collaboration with Keri Martinowich, we are studying mice with disruption of specific Bdnf promoters in order to determine the roles of individual promoters in the metabolic and neurcognitive phenotype of BDNF insufficiency. In collaboration with Matthew During, Louis Luttrell, Bronwen Martin, and Stuart Maudsley, multiple approaches to the treatment of BDNF insufficiency are currently under study.
Role of BDNF in Prader-Willi syndrome
We also studied patients with Prader-Willi syndrome (PWS), which is caused by a lack of paternally expressed genes on chromosome 15q11-13. Such patients typically present with hypotonia and poor feeding in the neonatal period followed by marked weight gain and severe hyperphagia between the ages of 1 and 5 years. PWS is also associated with cognitive impairment and behavioral abnormalities. In collaboration with Andrea Haqq, we conducted a pilot study comparing 13 PWS children with 13 age-/sex-matched lean controls and 13 age/sex/body mass index (BMI)–matched obese controls. We observed that patients with PWS had significantly lower serum BDNF than did the lean or obese controls. Lower serum BDNF suggests insufficient central nervous system production of BDNF because BDNF in peripheral circulation is believed to reflect cerebral output of BDNF. Decreased BDNF may be a cause for the disordered satiety and morbid obesity associated with PWS. BDNF insufficiency may also contribute to the neurocognitive abnormalities observed in PWS. We aim to confirm these findings in a larger cohort of patients with PWS and to examine possible associations between cognitive function and serum BDNF concentrations.
Role of BDNF in obesity and neurocognitive function
In addition, we are investigating the role of BDNF in other conditions associated with childhood obesity (e.g., melanocortin 4-receptor mutations in collaboration with Nancy Butte, Jonathan Krakoff, Ya-Xiong Tao, Marie Thearle, and William Knowler; and Smith-Magenis syndrome in collaboration with William Gahl and Ann Smith) and/or neurocognitive impairment (e.g. autism spectrum disorders, in collaboration with Susan Swedo's research group). We are also studying the role of single nucleotide polymorphisms of the BDNF gene locus in body-weight regulation and cognitive function in healthy adults and children from the general population. In collaboration with Joel Kleinman's research group, we are examining the associations of BDNF genotype with BMI and hypothalamic BDNF expression in cadaveric brain tissue from adult sudden-death victims. Because of BDNF's potential role in pain perception, we are also collaborating with Raymond Dionne and researchers at the Uniformed Service University of the Health Sciences and Walter Reed National Military Medical Center to explore possible associations between BDNF and phantom limb pain in amputees. Because various studies have shown that physical activity may play a role in modulating BDNF levels in the central nervous system, we are partnering with Katherine Warren and Pamela Wolters to study exercise, BDNF, and cognitive function in children who have undergone cranial radiation for treatment of brain tumors.
Role of leptin in ciliopathy-associated obesity syndromes
In collaboration with Leslie Biesecker's research group, we have been studying patients with Bardet-Biedl syndrome (BBS), a cilopathy associated with obesity. Animal models of cilia dysfunction have demonstrated defects in leptin receptor trafficking and signaling. In our human studies, we observed that patients with BBS (n=50) exhibit nearly two-fold higher serum leptin concentrations (p<0.001) than age/sex/race/BMI–matched control subjects (n=100). Hyperleptinemia out of proportion to the degree of adiposity suggests that leptin resistance may be the causative etiology of obesity in BBS. In collaboration with Pietro Maffei, Jürgen Naggert, and Meral Gunay-Aygun, we are currently seeking to replicate this observation in patients with Alström and Joubert syndromes, disorders distinct from BBS but also associated with ciliary dysfunction.
Studies on growth in children
In collaboration with Nelly Mauras, we have been studying children with constitutional delay of growth and maturation (CDGM), a condition characterized by short stature, delayed skeletal maturation, and late entry into puberty. In general, children with CDGM tend to be thin, with a growth pattern reminiscent of nutritional insufficiency. Our earlier investigations demonstrated higher total energy expenditure in boys with CDGM than in size-matched younger boys or in age-matched taller boys, suggesting a state of hypermetabolism, observations that led us to examine whether supplemental nutrition can augment growth in children with CDGM. Twenty prepubertal boys with CDGM were randomized (n=10/group) to 6 months' observation or daily nutritional supplementation, followed by additional daily growth hormone therapy in all subjects for another 12 months. Height, weight, lean body mass, hormones, and nutrition markers increased comparably in both groups through 18 months, indicating no additional benefit from nutritional supplementation. In collaboration with Robert Olney, we also examined the association between amino-terminal propeptide of C-type natriuretic peptide and height velocity (rate of gain in height) in healthy children.
- Childhood Brain Tumor Foundation (2012-2014): A Randomized Controlled Trial Evaluating a Physical Activity Intervention to Improve Cognitive Late Effects in Children with Brain Tumors Treated with Cranial Radiation
- NIH Bench-to-Bedside Award (2011–2012): Amitriptyline for the Treatment of BDNF Haploinsufficiency
- Prader-Willi Syndrome Association USA Grant (2010–2012): Brain-Derived Neurotrophic Factor in Prader-Willi Syndrome and MC4R Function-Altering Mutations
- Foundation for Prader-Willi Research Grant (2010–2012): The Relationship between Serum Brain-Derived Neurotrophic Factor (BDNF) Levels, BDNF Haplotypes and Neurocognitive Performance in Children with Prader-Willi Syndrome (PWS)
- Olney RC, Permuy JW, Prickett TC, Han JC, Espiner EA. Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) predicts height velocity in healthy children. Clin Endocrinol (Oxf) 2012;77:416-422.
- Feuillan PP, Ng D, Han JC, Sapp JC, Wetsch K, Spaulding E, Zheng YC, Caruso RC, Brooks BP, Johnston JJ, Yanovski JA, Biesecker LG. Patients with Bardet-Biedl syndrome have hyperleptinemia suggestive of leptin resistance. J Clin Endocrinol Metab 2011;96:E528-E535.
- Han JC, Damaso L, Welch S, Balagopal P, Hossain J, Mauras N. Effects of growth hormone and nutritional therapy in boys with constitutional growth delay: a randomized controlled trial. J Pediatr 2011;158:427-432.
- Han JC, Muehlbauer MJ, Cui HN, Newgard CB, Haqq AM. Lower brain-derived neurotrophic factor in patients with Prader-Willi syndrome compared to obese and lean control subjects. J Clin Endocrinol Metab 2010;95:3532-3536.
- Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS, Adler-Wailes DC, Sanford EL, Lacbawan FL, Uhl GR, Rennert OM, Yanovski JA. Brain-derived neurotrophic factor and obesity in the WAGR syndrome. N Engl J Med 2008;359:918-927.
- Schahram Akbarian, MD, PhD, Mount Sinai School of Medicine
- Leslie G. Biesecker, MD, Genetic Disease Research Branch, NHGRI, Bethesda, MD
- Nancy Butte, PhD, Baylor College of Medicine, Houston, TX
- Raymond A. Dionne, PhD, DDS, Division of Intramural Research, NINR, Bethesda, MD
- Matthew During, MD, DSc, Ohio State University College of Medicine, Columbus, OH
- William A. Gahl, MD, PhD, Clinical Director and Medical Genetics Branch, NHGRI, Bethesda, MD
- Meral Gunay-Aygun, MD, Johns Hopkins Children's Hospital, Baltimore, MD
- Andrea Haqq, MD, MHS, University of Alberta, Edmonton, Canada
- Joel E. Kleinman, MD, PhD, Clinical Brain Disorders Branch, NIMH, Bethesda, MD
- William C. Knowler, MD, PhD, MPH, Phoenix Epidemiology and Clinical Research Branch, NIDDK, Phoenix, AZ
- Jonathan A. Krakoff, MD, Phoenix Epidemiology and Clinical Research Branch, NIDDK, Phoenix, AZ
- Louis Luttrell, MD, PhD, Medical University of South Carolina, Charleston, SC
- Pietro Maffei, MD, PhD, Università degli Studi di Padova, Padua, Italy
- Bronwen M. Martin, PhD, Laboratory of Clinical Investigation, NIA, Baltimore, MD
- Keri Martinowich, PhD, Laboratory of Molecular Pathophysiology and Experimental Therapeutics, NIMH, Bethesda, MD
- Stuart R. Maudsley, PhD, Laboratory of Neurosciences, NIA, Baltimore, MD
- Nelly Mauras, MD, Nemours Children's Clinic, Jacksonville, FL
- Jürgen Naggert, PhD, Jackson Laboratory, Bar Harbor, ME
- Robert Olney, MD, Nemours Children's Clinic, Jacksonville, FL
- Margarita J. Raygada, PhD, Laboratory of Clinical and Developmental Genomics, NICHD, Bethesda, MD
- Owen M. Rennert, MD, Laboratory of Clinical and Developmental Genomics, NICHD, Bethesda, MD
- Martin Stofanko, PhD, Laboratorio GENE, Belo Horizonte, Brazil
- Ann C. Smith, MA, DSc (hon), Office of the Clinical Director, NHGRI, Bethesda, MD
- Susan E. Swedo, MD, Pediatrics and Developmental Neuropsychiatry Branch, NIMH, Bethesda, MD
- Ya-Xiong Tao, PhD, Auburn University College of Veterinary Medicine, Auburn, AL
- Marie S. Thearle, MD, MACP, Phoenix Epidemiology and Clinical Research Branch, NIDDK, Phoenix, AZ
- Jack W. Tsao, MD, DPhil, Uniformed Services University of the Health Sciences, Bethesda, MD
- Katherine E. Warren, MD, Pediatric Oncology Branch, NCI, Bethesda, MD
- Daniel R. Weinberger, MD, Clinical Brain Disorders Branch, NIMH, Bethesda, MD
- Pamela Wolters, PhD, Pediatric Oncology Branch, NCI, Bethesda, MD
- Jack A. Yanovksi, MD, PhD, Program on Developmental Endocrinology and Genetics, NICHD, Bethesda, MD