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Neuroendocrine Regulation of Metabolism and Neurocognition
- Joan C. Han, MD, Head, Unit on Metabolism and Neuroendocrinology
- Shannon R. Fuhr, BA, Postbaccalaureate Fellow
- Melanie D. Hicks, BA, Postbaccalaureate Fellow
- Amanda E. Huey, BA, Postbaccalaureate Fellow
- Alyson E. Spore, MSN, RN, Predoctoral Fellow
- Seo Yoon Chung, Special Volunteer
- Jamila R. Crossman, Special Volunteer
- Lindsay A. Hunter, BA, Special Volunteer
- Naomi A. Lisse, Special Volunteer
- Evguenia Morgun, Special Volunteer
- Zongyang Mou, Special Volunteer
- Chiew-Jen Ong, BS, Special Volunteer
- Sarah A. Siddiqui, Special Volunteer
- Matthew M. Tsang, Special Volunteer
- Emily G. Yin, 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 in healthy subjects as well as in 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 higher prevalence of childhood obesity and higher 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 display learning deficits, behavioral abnormalities, and decreased thermal pain response. In a cohort of 31 patients with WAGR syndrome, we observed that BDNF haploinsufficiency was associated with significantly lower 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. A treatment study using a BDNF agonist in patients with BDNF haploinsufficiency is being prepared.
BDNF in Prader-Willi syndrome
We have also been studying patients with Prader-Willi syndrome (PWS), which is caused by a lack of paternally expressed genes on chromosome 15q11-13. Patients with PWS 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. 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 potential 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.
BDNF in obesity and neurocognitive function
We are also investigating the role of BDNF in other conditions associated with childhood obesity (e.g., melanocortin 4-receptor mutations) 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. 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 adults with sudden death.
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 have observed that patients with BBS (n=50) have 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 degree of adiposity suggests that leptin resistance may be the causative etiology of obesity in BBS. We are currently seeking to replicate this observation in patients with Alström syndrome, a disorder that is distinct from BBS but is also associated with cilia dysfunction.
Nutritional therapy in boys with constitutional growth delay
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. These observations 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.
- NIH Bench-to-Bedside Award (2011–2013): Amitriptyline for the Treatment of BDNF Haploinsufficiency
- NICHD Bench-to-Bedside Research Award (2010–2012): The Role of BDNF in Autism Spectrum Disorder and Cognitive Function
- 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)
- 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, Lawlor DA, Kimm SY. Childhood obesity. Lancet 2010;375:1737-1748.
- 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.
- Dean E. Aria, DDS, Clinical Training Program, NIDCR, Bethesda, MD
- Leslie G. Biesecker, MD, Genetic Disease Research Branch, NHGRI, Bethesda, MD
- Carol W. Bassim, DMD, Clinical Research Core, NIDCR, Bethesda, MD
- Sheila M. Brady, RN, FNP, Program in Developmental Endocrinology and Genetics, NICHD, Bethesda, MD
- Carmen C. Brewer, PhD, Otolaryngology Branch, 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, NIH, Bethesda, MD
- Amber B. Courville, PhD, RD, Clinical Nutrition Service, Clinical Center, NIH, Bethesda, MD
- Raymond A. Dionne, DDS, PhD, Division of Intramural Research, NINR, Bethesda, MD
- Christine Golden-Williams, PhD, Neuroscience Branch, NIMH, Bethesda, MD
- Jennifer C. Graf, MS, RD, Clinical Nutrition Service, Clinical Center, NIH, Bethesda, MD
- Suvimol C. Hill, MD, Diagnostic Radiology Department, Clinical Center, NIH, Bethesda, MD
- Thomas M. Hyde, MD, PhD, The Genes, Cognition & Psychosis Program, NIMH, Bethesda, MD
- Joel E. Kleinman, MD, PhD, Clinical Brain Disorders Branch, NIMH, Bethesda, MD
- Jeffrey B. Kopp, MD, Kidney Diseases Branch, NIDDK, Bethesda, MD
- Merel Kozlosky, MS, RD, Clinical Nutrition Service, Clinical Center, NIH, Bethesda, MD
- Tanya J. Lehky, MD, Electromyography Section, NINDS, Bethesda, MD
- Barbara K. Lipska, PhD, Clinical Brain Disorders Branch, NIMH, Bethesda, MD
- 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
- David Ng, MD, Genetic Disease Research Branch, NHGRI, Bethesda, MD
- Carlo M. Pierpaoli, MD, PhD, Program on Pediatric Imaging and Tissue Sciences, NICHD, Bethesda, MD
- Margarita J. Raygada, PhD, Laboratory of Clinical Genomics, NICHD, Bethesda, MD
- Owen M. Rennert, MD, Laboratory of Clinical Genomics, NICHD, Bethesda, MD
- James C. Reynolds, MD, Diagnostic Radiology Department, Clinical Center, NIH, Bethesda, MD
- Lauren B. Shomaker, PhD, Program on Developmental Endocrinology and Genetics, NICHD, Bethesda, MD
- Susan E. Swedo, MD, Pediatrics and Developmental Neuropsychiatry Branch, NIMH, Bethesda, MD
- Lino Tessarollo, PhD, Mouse Cancer Genetics Program, NCI, Frederick, MD
- Daniel Driscoll, MD, PhD, University of Florida, Gainesville, FL
- Audrey E. Thurm, PhD, Pediatrics and Developmental Neuropsychiatry Branch, NIMH, Bethesda, MD
- Daniel R. Weinberger, MD, Clinical Brain Disorders Branch, NIMH, Bethesda, MD
- Jack A. Yanovksi, MD, PhD, Program on Developmental Endocrinology and Genetics, NICHD, Bethesda, MD
- Christopher K. Zalewski, MA, Otolaryngology Branch, NIDCD, Bethesda, MD
- Wadih M. Zein, MD, Ophthalmic Genetics and Visual Function Branch, NEI, Bethesda, MD
- Anthony Goldstone, MA, MRCP, PhD, Imperial College, London, UK
- Andrea Haqq, MD, MHS, University of Alberta, Edmonton, Canada
- Jessica Hellings, MD, University of Kansas Medical Center, Kansas City, KS
- Felicitas Lacbawan, MD, SUNY Downstate Medical Center, Brooklyn, NY
- Pietro Maffei, MD, PhD, Università degli Studi di Padova, Padua, Italy
- Jan Marshall, BSc, Jackson Laboratory, Bar Harbor, ME
- Nelly Mauras, MD, Nemours Children's Clinic, Jacksonville, FL
- Jennifer Miller, MD, University of Florida, Gainesville, FL
- Jürgen Naggart, PhD, Jackson Laboratory, Bar Harbor, ME
- James Resnick, PhD, University of Florida, Gainesville, FL
- Stephen Sharp, MD, Uniformed Services University of the Health Sciences, Bethesda, MD
- Marian Tanofsky-Kraff, PhD, Uniformed Services University of the Health Sciences, Bethesda, MD
- Jack Tsao, MD, DPhil, Uniformed Services University of the Health Sciences, Bethesda, MD