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Neuroendocrine Regulation of Metabolism and Neuro-Cognition

Joan C. Han, MD
  • Joan C. Han, MD, Head, Unit on Metabolism and Neuroendocrinology
  • Chen Lai, PhD, Research Collaborator
  • Alyson E. Spore, MSN, RN, Predoctoral Fellow
  • Melanie D. Hicks, BA, Postbaccalaureate Fellow
  • Daniela P. Reyes-Capo, BA, Postbaccalaureate Fellow
  • Gladys I. Palaguachi, BA, Special Volunteer
  • Bianca M. Williams, BA, Summer Intern
  • Yael H. Caplan, Special Volunteer
  • Meera M. Kattapuram, Special Volunteer
  • Rachel C. Kim, Special Volunteer
  • Mark D. Lee, Special Volunteer
  • Dmytro Mikhnev, Special Volunteer
  • Zongyang Mou, Special Volunteer
  • Tanvee Singh, Special Volunteer
  • Rujia Teng, Special Volunteer
  • Matthew M. Tsang, Special Volunteer

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 neuro-development. We hope that a better understanding of the pathophysiology of energy imbalance and cognitive impairment will lead to therapies for improving body composition and neuro-cognition.

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, cognitive impaiRment) syndrome, which is caused by heterozygous contiguous gene deletions of variable size in the chromosome 11p13 region.

Genotyping Methods:

We determine the 11p deletion boundaries using oligonucleotide array comparative genomic hybridization. In clinical practice, high-resolution karyotype and fluorescence in situ hybridization are also typically used for diagnosis. However, these methods can be costly and inaccessible in developing countries. Therefore, in collaboration with Martin Stofanko, we developed a novel quantitative fluorescent PCR method for rapid and inexpensive screening of genomic copy number variations for the diagnosis of WAGR syndrome and other deletion/duplication syndromes (1).

Obesity:

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 (N Engl J Med 2008;359:918). 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. Studies are currently under way to examine energy balance, body composition, and metabolic complications in patients with WAGR syndrome.

Pain Perception:

Bdnf+/− mice are not only hyperphagic and obese but also exhibit reduced thermal pain response, leading us to examine nociception in 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 (N Engl J Med 2008;359:918). 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.

Cognition and Behavior:

Bdnf+/− mice also exhibit learning deficits and social behavior abnormalities, which led us to examine these features in human patients. We observed that, among patients with WAGR syndrome, BDNF haploinsufficiency is associated with a 20-pointed lower intelligence quotient and 15-point lower Vineland Adaptive Behavior Composite score (2) than among individuals without the haploinsufficiency. BDNF haploinsufficiency was also associated with greater social impairment, the percentage meeting criteria for autism on the Autism Diagnostic Interview-Revised, but not for diagnosis of true autism based on Autism Diagnostic Observation Schedule and the clinical judgment of a child psychologist (2). Our findings support a role for BDNF in human neuro-cognitive development.

PAX6 Haploinsufficiency:

The aniridia of WAGR syndrome is caused by PAX6 haploinsufficiency. The gene is also believed to play a role in the development of the pineal, the gland that controls the circadian rhythm and produces the sleep hormone melatonin. Our group is currently examining pineal size, melatonin production, and sleep in patients with WAGR syndrome and isolated aniridia. We are also investigating other abnormalities that may be associated with PAX6 haploinsufficiency, including auditory processing disorders, structural brain abnormalities, and eye movement defects.

Collaborative Studies:

In collaboration with Keri Martinowich, we are studying mice with disruption of specific Bdnf promoters in order to determine their roles in the metabolic and neuro-cognitive phenotype of BDNF insufficiency. In collaboration with Matthew During, Jessica Hellings, Louis Luttrell, Bronwen Martin, and Stuart Maudsley, several approaches to the treatment of BDNF insufficiency are currently under study.

Role of BDNF in the 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 (J Clin Endocrinol Metab 2010;95:3532). Lower serum BDNF suggests insufficient central nervous system production of BDNF given that BDNF in peripheral circulation is believed to reflect cerebral output of BDNF. Reduced BDNF may be a cause for the disordered satiety and morbid obesity associated with PWS. BDNF insufficiency may also contribute to the neuro-cognitive abnormalities observed in PWS. We aim to confirm these findings in a larger cohort of patients with PWS, including younger children who have not yet developed hyperphagia symptoms. We also are examining possible associations between cognitive function and serum BDNF concentrations.

Role of BDNF in obesity and neuro-cognitive function

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 neuro-cognitive 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 demonstrated defects in leptin receptor trafficking and signaling. In our human studies, we observed that patients with BBS exhibit nearly two-fold higher serum leptin concentrations (p<0.001) than age/sex/race/BMI–matched control subjects (J Clin Endocrinol Metab 2011;96:E528) and display higher hyperphagia questionnaire scores (3). 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.

Other genes associated with obesity

In collaboration with George Uhl, we examined the role of SLC6A15, a gene that encodes a sodium-dependent transporter of leucine and other branched chain amino acids, in obesity and insulin resistance (4). In collaboration with Rudolph Leibel, Wendy Chung, and Nazrat Mirza, we identified patients with novel frameshift mutations in LEPR, the gene encoding the leptin receptor (5). We continue to enroll patients with severe obesity in childhood in an effort to identify novel genes important for energy homeostasis.

Additional Funding

  • Childhood Brain Tumor Foundation (2012): A Randomized Controlled Trial Evaluating a Physical Activity Intervention to Improve Cognitive Late Effects in Children with Brain Tumors Treated with Cranial Radiation (ongoing)
  • Prader-Willi Syndrome Association USA Grant (2010): Brain-Derived Neurotrophic Factor in Prader-Willi Syndrome and MC4R Function-Altering Mutations (ongoing)
  • Foundation for Prader-Willi Research Grant (2010): The Relationship between Serum Brain-Derived Neurotrophic Factor (BDNF) Levels, BDNF Haplotypes and Neurocognitive Performance in Children with Prader-Willi Syndrome (PWS) (ongoing)

Publications

  1. Stofanko M, Han JC, Sarah H. Elsea SH, Pena HB, Gonçalves-Dornelas H, Pena SDJ. Rapid and inexpensive screening of genomic copy number variations using a novel quantitative fluorescent PCR method. Disease Markers 2013;35:589-594.
  2. Han JC, Thurm A, Williams CG, Joseph LA, Zein WM, Brooks BP, Butman JA, Brady SM, Fuhr SR, Hicks MD, Huey AE, Hanish AE, Danley KM, Raygada MJ, Rennert OM, Martinowich K, Sharp SJ, Tsao JW, Swedo SE. Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome. Cortex 2013;Epub ahead of print.
  3. Sherafat-Kazemzadeh R, Ivey L, Kahn SR, Sapp JC, Hicks MD, Kim RC, Krause AJ, Shomaker LB, Biesecker LG, Han JC, Yanovski JA. Hyperphagia among patients with Bardet-Biedl syndrome. Pediatr Obes 2013;8:E64-7.
  4. Drgonova J, Jacobsson JA, Han JC, Yanovski JA, Fredriksson R, Marcus C, Schiöth HB, Uhl GR. Involvement of the neutral amino acid transporter SLC6A15 and leucine in obesity-related phenotypes. PLoS One 2013;8:e68245.
  5. Gill R, Him Cheung Y, Shen Y, Lanzano P, Mirza NM, Ten S, Maclaren NK, Motaghedi R, Han JC, Yanovski JA, Leibel RL, Chung WK. Whole-exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity. Obesity 2013;Epub ahead of print.

Collaborators

  • Leslie G. Biesecker, MD, Genetic Disease Research Branch, NHGRI, Bethesda, MD
  • Carmen C. Brewer, PhD, Audiology Unit, NIDCD, Bethesda, MD
  • Brian P. Brooks, MD, PhD, Ophthalmic Genetics and Visual Function Branch, NEI, Bethesda, MD
  • John A. Butman, MD, PhD, Radiology and Imaging Sciences, Clinical Center, Bethesda, MD
  • Nancy Butte, PhD, Baylor College of Medicine, Houston, TX
  • Wendy K. Chung, MD, PhD, Columbia University Medical Center, New York, NY
  • Raymond A. Dionne, PhD, DDS, East Carolina University, Greenville, NC
  • 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 Center, Baltimore, MD
  • Andrea Haqq, MD, MHS, University of Alberta, Edmonton, Canada
  • Jessica A. Hellings, MD, Ohio State University, Columbus, OH
  • 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
  • Francois M. LaLonde, PhD, Child Psychiatry Branch, NIMH, Bethesda, MD
  • Rudolph L. Leibel, MD, Columbia University Medical Center, New York, NY
  • 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, The Lieber Institute for Brain Development, Baltimore, MD
  • Stuart R. Maudsley, PhD, Laboratory of Neurosciences, NIA, Baltimore, MD
  • Nazrat Mirza, MD, Children's National Medical Center, Washington, DC
  • 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
  • Armin Raznahan, MD, PhD, Section on Developmental Brain Imaging, NIMH, Bethesda, MD
  • Owen M. Rennert, MD, Laboratory of Clinical and Developmental Genomics, NICHD, Bethesda, MD
  • Ann C. Smith, MA, DSc (hon), Office of the Clinical Director, NHGRI, Bethesda, MD
  • Martin Stofanko, PhD, Laboratorio GENE, Belo Horizonte, Brazil
  • Susan E. Swedo, MD, Pediatrics and Developmental Neuroscience 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
  • Audrey Thurm, PhD, Pediatrics and Developmental Neuroscience Branch, NIMH, Bethesda, MD
  • Jack W. Tsao, MD, DPhil, Uniformed Services University of the Health Sciences, Bethesda, MD
  • George R. Uhl, MD, PhD, Molecular Neurobiology Branch, NIDA, Baltimore, MD
  • Katherine E. Warren, MD, Pediatric Oncology Branch, NCI, 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
  • Wadih M. Zein, MD, Ophthalmic Genetics and Visual Function Branch, NEI, Bethesda, MD

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