A5072252739- Regulation of Appetite and Obesity
- Biochemical Analysis and Sensing Techniques
- Adipose Tissue and Metabolism
- Pancreatic function and diabetes
- Adipokines, Inflammation, and Metabolic Diseases
- Genetic Associations and Epidemiology
- Receptor Mechanisms and Signaling
- Dietary Effects on Health
- Genomic variations and chromosomal abnormalities
- Circadian rhythm and melatonin
- Genetics and Neurodevelopmental Disorders
- Hypothalamic control of reproductive hormones
- melanin and skin pigmentation
- Neurogenesis and neuroplasticity mechanisms
- Sleep and related disorders
- Hormonal Regulation and Hypertension
- Thyroid Disorders and Treatments
- Nerve injury and regeneration
- Congenital heart defects research
- Cytokine Signaling Pathways and Interactions
- Epigenetics and DNA Methylation
- Advanced Glycation End Products research
- Neuroendocrine regulation and behavior
- Advanced Fluorescence Microscopy Techniques
- Lipid metabolism and disorders
University of Cambridge
2016-2025
NIHR Cambridge Biomedical Research Centre
2011-2025
Addenbrooke's Hospital
2016-2025
MRC Epidemiology Unit
2025
Wellcome/MRC Institute of Metabolic Science
2014-2024
Cambridge Quantum Computing (United Kingdom)
2024
Wellcome Trust
2013-2021
National Institute for Health Research
2011-2021
Medical Research Council
2014-2021
Nederlands Instituut Voor Zuivel Oonderzoek
2015
Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, clinical spectrum and mode inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, there little information regarding genotype-phenotype correlations.We determined nucleotide sequence MC4R gene in 500 probands with severe childhood Family studies were undertaken examine cosegregation identified mutations Subjects underwent metabolic endocrine...
The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for existence multiple physiological functions this hormone rodents. In contrast, information regarding roles humans is limited. Three morbidly obese children, who were congenitally deficient leptin, treated with daily subcutaneous injections recombinant human up to 4 years sustained, beneficial effects on appetite, fat mass,...
The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for existence multiple physiological functions this hormone rodents. In contrast, information regarding roles humans is limited. Three morbidly obese children, who were congenitally deficient leptin, treated with daily subcutaneous injections recombinant human up to 4 years sustained, beneficial effects on appetite, fat mass,...
Over 20 severely obese subjects in 11 independent kindreds have been reported to pathogenic heterozygous mutations the gene encoding melanocortin 4 receptor (MC4R), making this most common known monogenic cause of human obesity. To date, detailed clinical phenotype dominantly inherited disorder has not defined, and no homozygous described. We determined nucleotide sequence entire coding region MC4R 243 with severe, early-onset A novel two–base pair GT insertion codon 279 was found two...
A single family has been described in which obesity results from a mutation the leptin-receptor gene (LEPR), but prevalence of such mutations severe, early-onset not systematically examined.We sequenced LEPR 300 subjects with hyperphagia and severe obesity, including 90 probands consanguineous families, investigated extent to cosegregated affected receptor function. We evaluated metabolic, endocrine, immune function relatives.Of subjects, 8 (3%) had nonsense or missense mutations--7 were...
Studies of the fat-derived hormone leptin have provided key insights into molecular and neural components feeding behavior body weight regulation. An important challenge lies in understanding how rewarding properties food interact with, can override, physiological satiety signals promote overeating. We used functional magnetic resonance imaging to measure brain responses two human patients with congenital deficiency who were shown images before after 7 days replacement therapy. Leptin was...
The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased intake obesity, as well hyperactivity. We report an 8-year-old girl with hyperphagia severe impaired cognitive function, hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), region encompassing the gene. have identified proximal inversion breakpoint that lies 850 kb telomeric 5′ end patient’s genomic DNA was heterozygous...
Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated the control of energy balance rodents, but there no information regarding such an association humans.We assessed pressure, heart rate, urinary catecholamines overweight or obese subjects a loss-of-function mutation MC4R, gene encoding melanocortin 4 receptor, equally subjects. We also examined effects MC4R agonist administered for 7 days 28...
Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role central nervous (CNS-Mcr) in control adiposity through effects on nutrient partitioning and cellular lipid metabolism independent intake. report that pharmacological inhibition receptors (Mcr) rats genetic disruption Mc4r mice directly potently promoted uptake, triglyceride synthesis, fat accumulation white adipose tissue (WAT), while increased CNS-Mcr triggered mobilization. These...
Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that increase leptin levels seen diet-induced obesity (DIO) drives an BP rodents, effect was not animals deficient or receptors (LepR). Furthermore, humans loss-of-function mutations and LepR have low despite severe obesity. Leptin's effects on are mediated by neuronal circuits dorsomedial hypothalamus (DMH), as blocking a specific antibody, antagonist, inhibition...
Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental skeletal dysplasia, severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, identified de novo heterozygous nonsense mutation in gene encoding receptor (THRA) generating mutant protein that inhibits wild-type action dominant negative manner. Our observations...
Genetic studies in patients with severe early-onset obesity have provided insights into the molecular and physiological pathways that regulate body weight humans. We report a 19-year-old male hyperphagia obesity, mild learning difficulties hypogonadism, whom diagnostic tests for Prader-Willi syndrome (PWS) had been negative. carried out detailed clinical metabolic phenotyping of this patient investigated genetic basis using Agilent 185 k array comparative genomic hybridization (aCGH)...
Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role brain-expressed 2 protein (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion Mrap2, both which develop severe obesity at a young age. Mrap2 interacts directly 4 (Mc4r), previously implicated mammalian obesity, it enhances Mc4r-mediated generation second messenger cyclic adenosine monophosphate, suggesting that...
Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads weight loss in diet-induced obese animals and individuals with complete POMC deficiency. While deficiency very rare, 1–5% of severely harbor heterozygous mutations MC4R. We sought assess efficacy human studied effects mutant MC4Rs cells response administration rodent studies clinical trial. annotated...
The functional loss of both alleles the human pro-opiomelanocortin (POMC) gene leads to a very rare syndrome hypoadrenalism, red hair and early-onset obesity. In order examine whether more subtle genetic variants in POMC might contribute obesity, coding region was sequenced 262 Caucasian subjects with history severe obesity from childhood. Two children were found be heterozygous for missense mutation, R236G, which disrupts dibasic cleavage site between beta melanocyte-stimulating hormone...
Mutations in the melanocortin-4 receptor gene (MC4R) represent commonest monogenic cause of human obesity. However, information regarding precise effects such mutations on function is very limited. We examined functional properties 12 different MC4R that result severe, familial, early-onset Of nine missense mutants studied, four were completely unable to generate cAMP response ligand and five partially impaired. Four showed evidence impaired cell surface expression six reduced binding...
Congenital deficiency of proopiomelanocortin (POMC) results in a syndrome hypoadrenalism, severe obesity, and altered skin hair pigmentation. The concept that subtle variation POMC expression and/or function might contribute to common obesity is suggested by studies reporting linkage obesity-related traits locus on chromosome 2p22 encompassing the gene. We identified novel homozygous frameshift (C6906del) mutation child Turkish origin with hypoadrenalism. This would be predicted lead loss...
Context: Congenital deficiency of the neuroendocrine-specific enzyme prohormone convertase (PC) 1/3 leads to a syndrome characterized by obesity, small intestinal dysfunction, and dysregulation glucose homeostasis in humans. To date, only two unrelated subjects with this disorder have been reported.