Stephen O'Rahilly

Summary

Affiliation: University of Cambridge
Country: UK

Publications

  1. ncbi request reprint Genetic factors in type 2 diabetes: the end of the beginning?
    Stephen O'Rahilly
    University of Cambridge, Department of Clinical Biochemistry, Addenbrooke s Hospital, Cambridge CB2 2QQ, UK
    Science 307:370-3. 2005
  2. doi request reprint Genetic syndromes of severe insulin resistance
    Robert K Semple
    Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke s Hospital, Cambridge, United Kingdom
    Endocr Rev 32:498-514. 2011
  3. pmc The hormonal control of food intake
    Anthony P Coll
    Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge CB2 2XY, United Kingdom
    Cell 129:251-62. 2007
  4. doi request reprint Human genetics illuminates the paths to metabolic disease
    Stephen O'Rahilly
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0QQ, UK
    Nature 462:307-14. 2009
  5. doi request reprint Human obesity as a heritable disorder of the central control of energy balance
    S O'Rahilly
    Department of Clinical Biochemistry, Institute of Metabolic Science, Addenbrooke s Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK
    Int J Obes (Lond) 32:S55-61. 2008
  6. ncbi request reprint Human obesity and insulin resistance: lessons from experiments of nature
    S O'Rahilly
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QQ, UK
    Biochem Soc Trans 35:33-6. 2007
  7. pmc C/EBP transcription factors regulate SREBP1c gene expression during adipogenesis
    Victoria A Payne
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0QQ, UK
    Biochem J 425:215-23. 2010
  8. ncbi request reprint Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma
    David B Savage
    Department of Medicine, Addenbrooke s Hospital, Cambridge, UK
    Diabetes 52:910-7. 2003
  9. ncbi request reprint Regional differences in the response of human pre-adipocytes to PPARgamma and RXRalpha agonists
    Ciaran P Sewter
    University of Cambridge, Departments of Medicine and Clinical Biochemistry, Addenbrooke s Hospital, Cambridge, United Kingdom
    Diabetes 51:718-23. 2002
  10. ncbi request reprint Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis
    Christopher J Lelliott
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK
    FASEB J 19:1108-19. 2005

Detail Information

Publications96

  1. ncbi request reprint Genetic factors in type 2 diabetes: the end of the beginning?
    Stephen O'Rahilly
    University of Cambridge, Department of Clinical Biochemistry, Addenbrooke s Hospital, Cambridge CB2 2QQ, UK
    Science 307:370-3. 2005
    ....
  2. doi request reprint Genetic syndromes of severe insulin resistance
    Robert K Semple
    Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke s Hospital, Cambridge, United Kingdom
    Endocr Rev 32:498-514. 2011
    ..We now review recent developments in understanding of genetic forms of severe insulin resistance and/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlying pathophysiology...
  3. pmc The hormonal control of food intake
    Anthony P Coll
    Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge CB2 2XY, United Kingdom
    Cell 129:251-62. 2007
    ..These hormones come from three major sites-fat cells, the gastrointestinal tract, and the pancreas. In this Review we provide a synthesis of recent evidence concerning the actions of these hormones on food intake...
  4. doi request reprint Human genetics illuminates the paths to metabolic disease
    Stephen O'Rahilly
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0QQ, UK
    Nature 462:307-14. 2009
    ....
  5. doi request reprint Human obesity as a heritable disorder of the central control of energy balance
    S O'Rahilly
    Department of Clinical Biochemistry, Institute of Metabolic Science, Addenbrooke s Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK
    Int J Obes (Lond) 32:S55-61. 2008
    ..Indeed, we hope that they may eventually lead to improved treatment for patients and, in addition, help to inculcate a more enlightened attitude to the obese with a reduction in their experience of social and economic discrimination...
  6. ncbi request reprint Human obesity and insulin resistance: lessons from experiments of nature
    S O'Rahilly
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QQ, UK
    Biochem Soc Trans 35:33-6. 2007
    ..Ultimately, this is a potential route to treatment of both disease types. This approach is discussed in relation to Type 2 diabetes, arising from both insufficient insulin production and insulin resistance...
  7. pmc C/EBP transcription factors regulate SREBP1c gene expression during adipogenesis
    Victoria A Payne
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0QQ, UK
    Biochem J 425:215-23. 2010
    ..Moreover, the findings of the present study identify an important additional mechanism via which the C/EBP transcription factors may control a network of gene expression regulating adipogenesis, lipogenesis and insulin sensitivity...
  8. ncbi request reprint Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma
    David B Savage
    Department of Medicine, Addenbrooke s Hospital, Cambridge, UK
    Diabetes 52:910-7. 2003
    ..Although the condition is rare, the study of humans with dominant-negative mutations in PPAR-gamma can provide important insight into the roles of this nuclear receptor in human metabolism...
  9. ncbi request reprint Regional differences in the response of human pre-adipocytes to PPARgamma and RXRalpha agonists
    Ciaran P Sewter
    University of Cambridge, Departments of Medicine and Clinical Biochemistry, Addenbrooke s Hospital, Cambridge, United Kingdom
    Diabetes 51:718-23. 2002
    ....
  10. ncbi request reprint Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis
    Christopher J Lelliott
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK
    FASEB J 19:1108-19. 2005
    ..Given the broader importance of hepatic steatosis, the novel molecular mechanism revealed in this study should be examined in other forms of steatosis and nonalcoholic steatohepatitis...
  11. pmc Loss of agouti-related peptide does not significantly impact the phenotype of murine POMC deficiency
    Marcus P Corander
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Level 4, Addenbrooke s Hospital, Cambridge, UK
    Endocrinology 152:1819-28. 2011
    ..If AgRP has significant melanocortin-independent actions, these are of insufficient magnitude in vivo to impact any of the detailed phenotypes we have measured under a wide variety of conditions...
  12. doi request reprint Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity
    Eleanor Wheeler
    Wellcome Trust Sanger Institute, Cambridge, UK
    Nat Genet 45:513-7. 2013
    ..0001). Integrative gene network pathway analysis of rare deletions indicated enrichment of genes affecting G protein-coupled receptors (GPCRs) involved in the neuronal regulation of energy homeostasis...
  13. ncbi request reprint A de novo mutation affecting human TrkB associated with severe obesity and developmental delay
    Giles S H Yeo
    University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge CB2 2XY, UK
    Nat Neurosci 7:1187-9. 2004
    ..The associated impairment in memory, learning and nociception seen in the proband reflects the crucial role of TrkB in the human nervous system...
  14. pmc ETO/MTG8 is an inhibitor of C/EBPbeta activity and a regulator of early adipogenesis
    Justin J Rochford
    Department of Clinical Biochemistry, University of Cambridge, Box 232, Level 4, Addenbrooke s Hospital, Hills Rd, Cambridge CB2 2QR, United Kingdom
    Mol Cell Biol 24:9863-72. 2004
    ..These findings define, for the first time, a molecular role for ETO in normal physiology as an inhibitor of C/EBPbeta and a novel regulator of early adipogenesis...
  15. ncbi request reprint Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha
    Ciaran Sewter
    Department of Clinical Biochemistry and Medicine, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK
    Diabetes 51:1035-41. 2002
    ..The specific reduction in the SREBP1c isoform seen in the adipose tissue of obese and type 2 diabetic subjects can be recapitulated ex vivo by TNF-alpha, suggesting a possible mechanism for this association...
  16. pmc Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor
    I Sadaf Farooqi
    Cambridge Institute for Medical Research, University Department of Clinical Biochemistry, Addenbrooke s Hospital, Cambridge, United Kingdom
    N Engl J Med 356:237-47. 2007
    ..A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined...
  17. pmc A family with severe insulin resistance and diabetes due to a mutation in AKT2
    Stella George
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QQ, UK
    Science 304:1325-8. 2004
    ..These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans...
  18. ncbi request reprint The metabolic syndrome: peroxisome proliferator-activated receptor gamma and its therapeutic modulation
    Mark Gurnell
    Department of Medicine, University of Cambridge, Addenbrooke s Hospital, Cambridge CB2 2QQ, United Kingdom
    J Clin Endocrinol Metab 88:2412-21. 2003
    ..These studies provide further support for the future development of more selective receptor modulators, targeting specific pathways to ameliorate facets of the metabolic syndrome...
  19. pmc The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation
    Victoria A Payne
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, Cambridge, UK
    Diabetes 57:2055-60. 2008
    ..Therefore, we examined whether BSCL2 is involved in the regulation of adipocyte differentiation and the mechanism whereby pathogenic mutations in BSCL2 cause lipodystrophy...
  20. ncbi request reprint The peroxisome proliferator-activated receptor-gamma regulates murine pyruvate carboxylase gene expression in vivo and in vitro
    Sarawut Jitrapakdee
    Cambridge Institute of Diabetes, Endocrinology, and Metabolism and the Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Cambridge, CB2 2QR, United Kingdom
    J Biol Chem 280:27466-76. 2005
    ..Our findings identified PC as a PPARgamma-regulated gene and suggested a role for PPARgamma regulating intermediary metabolism...
  21. pmc Rare variants in single-minded 1 (SIM1) are associated with severe obesity
    Shwetha Ramachandrappa
    University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke s Hospital, Cambridge, United Kingdom
    J Clin Invest 123:3042-50. 2013
    ..The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling. ..
  22. ncbi request reprint Energy expenditure and adaptive responses to an acute hypercaloric fat load in humans with lipodystrophy
    David B Savage
    Department of Clinical Biochemistry and Medicine, Level 4, Box 232, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom
    J Clin Endocrinol Metab 90:1446-52. 2005
    ..Insight into the molecular mechanisms responsible for this phenomenon may yield novel therapeutic approaches for obesity...
  23. ncbi request reprint Monogenic obesity in humans
    I Sadaf Farooqi
    Departments of Medicine and Clinical Biochemistry, Cambridge University, Addenbrooke s Hospital, Cambridge CB2 2QQ, UK
    Annu Rev Med 56:443-58. 2005
    ..Practical implications of these findings for genetic counseling, prognostication, and even therapy have already emerged...
  24. ncbi request reprint Obesity therapy: altering the energy intake-and-expenditure balance sheet
    Vivion E F Crowley
    University Departments of Medicine and Clinical Biochemistry, Addenbrooke s Hospital, Cambridge CB2 2QR, UK
    Nat Rev Drug Discov 1:276-86. 2002
    ..This review focuses on how fat mass can be reduced by altering the balance between energy intake and expenditure...
  25. pmc Large, rare chromosomal deletions associated with severe early-onset obesity
    Elena G Bochukova
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, Cambridge CB2 0QQ, UK
    Nature 463:666-70. 2010
    ..Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity...
  26. pmc Common variants near MC4R are associated with fat mass, weight and risk of obesity
    Ruth J F Loos
    MRC Epidemiology Unit, Addenbrooke s Hospital, Cambridge CB2 0QQ, UK
    Nat Genet 40:768-75. 2008
    ....
  27. ncbi request reprint Studies of the neuromedin U-2 receptor gene in human obesity: evidence for the existence of two ancestral forms of the receptor
    Sumit Bhattacharyya
    University of Cambridge, Department of Medicine, Box 232, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QQ, UK
    J Endocrinol 183:115-20. 2004
    ..Further investigation of the pharmacogenomic consequences of NMU2R variation in humans is warranted...
  28. ncbi request reprint Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor gamma function (P465L PPARgamma) in mice
    Sarah L Gray
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QR, UK
    Diabetes 55:2669-77. 2006
    ..Thus, adipose tissue expandability is identified as an important factor for the development of insulin resistance in the context of positive energy balance...
  29. pmc Functional characterization and structural modeling of obesity associated mutations in the melanocortin 4 receptor
    Karen Tan
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, Box 289, Hills Road, Cambridge CB2 2QQ, United Kingdom
    Endocrinology 150:114-25. 2009
    ..The combination of functional studies and structural modeling of naturally occurring pathogenic mutations in MC4R can provide valuable information regarding the molecular mechanism of MC4R activation and its dysfunction in human disease...
  30. pmc TCF7L2 polymorphisms modulate proinsulin levels and beta-cell function in a British Europid population
    Ruth J F Loos
    Medical Research Council Epidemiology Unit, Strangeways Research Laboratory, Cambridge, UK
    Diabetes 56:1943-7. 2007
    ....
  31. ncbi request reprint Proopiomelanocortin-deficient mice are hypersensitive to the adverse metabolic effects of glucocorticoids
    Anthony P Coll
    University Department of Medicine, Addenbrooke s Hospital, Cambridge CB2 2QR, UK
    Diabetes 54:2269-76. 2005
    ..This may occur through a mechanism involving the suppression of AgRP by the hypoadrenal state...
  32. pmc Mitochondrial dysfunction in patients with primary congenital insulin resistance
    Alison Sleigh
    Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, United Kingdom
    J Clin Invest 121:2457-61. 2011
    ....
  33. pmc Sequential regulation of diacylglycerol acyltransferase 2 expression by CAAT/enhancer-binding protein beta (C/EBPbeta) and C/EBPalpha during adipogenesis
    Victoria A Payne
    Department of Clinical Biochemistry, University of Cambridge, Box 232, Level 4, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QR, United Kingdom
    J Biol Chem 282:21005-14. 2007
    ..Moreover, they further refine the complex and serial roles of the C/EBP family of transcription factors in inducing and maintaining the metabolic properties of mature adipocytes...
  34. ncbi request reprint Studies of the peptide YY and neuropeptide Y2 receptor genes in relation to human obesity and obesity-related traits
    Chiao Chien Connie Hung
    University Department of Clinical Biochemistry, Addenbrookes Hospital, Cambridge, CB2 2QQ, UK
    Diabetes 53:2461-6. 2004
    ..01). In conclusion, mutations in PYY and Y2R are not commonly found in humans with severe early-onset obesity. The relationship between common variants in Y2R and obesity-related traits deserves further exploration in other populations...
  35. pmc Role for the obesity-related FTO gene in the cellular sensing of amino acids
    Pawan Gulati
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke s Hospital, Cambridge CB2 0QQ, United Kingdom
    Proc Natl Acad Sci U S A 110:2557-62. 2013
    ..We describe a role for FTO in the coupling of amino acid levels to mammalian target of rapamycin complex 1 signaling. These findings suggest that FTO may influence body composition through playing a role in cellular nutrient sensing...
  36. doi request reprint Metabolic insights from extreme human insulin resistance phenotypes
    Anna Stears
    Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge, UK
    Best Pract Res Clin Endocrinol Metab 26:145-57. 2012
    ....
  37. doi request reprint Plasma adiponectin as a marker of insulin receptor dysfunction: clinical utility in severe insulin resistance
    Robert K Semple
    Institute of Metabolic Science, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK
    Diabetes Care 31:977-9. 2008
    ..Our previous observation of paradoxical hyperadiponectinemia in insulin receptoropathy provides a possible basis for a simpler and cheaper screening test...
  38. ncbi request reprint Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene
    I Sadaf Farooqi
    University Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, United Kingdom
    N Engl J Med 348:1085-95. 2003
    ..However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype-phenotype correlations...
  39. pmc Comment on "A common genetic variant is associated with adult and childhood obesity"
    Ruth J F Loos
    Medical Research Council Epidemiology Unit, Cambridge, UK
    Science 315:187; author reply 187. 2007
    ..However, we found no evidence of association between rs7566605 and body mass index in two large ethnically homogeneous population-based cohorts. On the contrary, an opposite tendency was observed...
  40. pmc Leptin regulates peripheral lipid metabolism primarily through central effects on food intake
    Xavier Prieur
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, Cambridge CB2 OQQ, United Kingdom
    Endocrinology 149:5432-9. 2008
    ..Whereas we cannot exclude direct peripheral effects of leptin on certain aspects of lipid metabolism, we were unable to detect any such effects on the parameters measured in this study...
  41. ncbi request reprint The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis
    Constantinos Christodoulides
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2QR, UK
    J Cell Sci 119:2613-20. 2006
    ..Given the public health importance of disorders of adipose mass, further knowledge of the pathways involved specifically in human adipocyte differentiation might ultimately be of clinical relevance...
  42. doi request reprint Treatment with recombinant human insulin-like growth factor (rhIGF)-I/rhIGF binding protein-3 complex improves metabolic control in subjects with severe insulin resistance
    Fiona M Regan
    University of Cambridge, Department of Pediatrics, Cambridge, United Kingdom
    J Clin Endocrinol Metab 95:2113-22. 2010
    ..We report clinical and physiological outcomes after adjunctive therapy with rhIGF-I/rhIGFBP-3 in five subjects with SIR...
  43. ncbi request reprint Association between physical activity and blood pressure is modified by variants in the G-protein coupled receptor 10
    Paul W Franks
    University of Cambridge, Department of Public Health and Primary Care, Cambridge, UK
    Hypertension 43:224-8. 2004
    ..Knowledge of GPR10 genotype may define those who are least likely to benefit from physical activity. These findings may have relevance in the targeted treatment of hypertensive disease...
  44. doi request reprint Lipodystrophy: metabolic insights from a rare disorder
    Isabel Huang-Doran
    Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK
    J Endocrinol 207:245-55. 2010
    ....
  45. ncbi request reprint The link between nutritional status and insulin sensitivity is dependent on the adipocyte-specific peroxisome proliferator-activated receptor-gamma2 isoform
    Gema Medina-Gomez
    Department of Clinical Biochemistry, University of Cambridge Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QR, UK
    Diabetes 54:1706-16. 2005
    ....
  46. ncbi request reprint Sequence variants in the melatonin-related receptor gene (GPR50) associate with circulating triglyceride and HDL levels
    Sumit Bhattacharyya
    Department of Medicine, University of Cambridge, Cambridge, UK
    J Lipid Res 47:761-6. 2006
    ..39 mM) than wild-type subjects (1.47 mM) (P < 0.01). These findings suggest a previously unexpected role for this orphan receptor in the regulation of lipid metabolism that warrants further investigation...
  47. pmc Human frame shift mutations affecting the carboxyl terminus of perilipin increase lipolysis by failing to sequester the adipose triglyceride lipase (ATGL) coactivator AB-hydrolase-containing 5 (ABHD5)
    Sheetal Gandotra
    Institute of Metabolic Science Metabolic Research Laboratories and the Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Cambridge CB2 0QQ, United Kingdom
    J Biol Chem 286:34998-5006. 2011
    ..The data also suggest that pharmacological inhibition of ATGL could have therapeutic potential in patients with this rare but metabolically serious disorder...
  48. ncbi request reprint A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance
    Yung Seng Lee
    University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, CB2 2XY, United Kingdom
    Cell Metab 3:135-40. 2006
    ..Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for beta-MSH in the control of human energy homeostasis...
  49. pmc Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile
    Tuomas O Kilpeläinen
    Medical Research Council MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK
    Nat Genet 43:753-60. 2011
    ..Our findings provide new insights into adiposity and insulin resistance...
  50. ncbi request reprint Heterozygosity for a POMC-null mutation and increased obesity risk in humans
    I Sadaf Farooqi
    University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, CB2 2XY, UK
    Diabetes 55:2549-53. 2006
    ..191. We conclude that loss of one copy of the POMC gene predisposes to obesity in humans. Thus, genetic variants having relatively subtle effects on POMC expression and function could influence susceptibility to obesity...
  51. pmc A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice
    David B Savage
    Department of Clinical Biochemistry and Medicine, University of Cambridge, Cambridge, United Kingdom
    PLoS Med 5:e27. 2008
    ..However, the functional implications of the mutation were not known. The objective of this study was to characterise the molecular and physiological consequences of this genetic variant...
  52. pmc Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice
    Xavier Prieur
    Institute of Metabolic Science, Metabolic Research Laboratories, and Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK
    Diabetes 60:797-809. 2011
    ....
  53. ncbi request reprint Does physical activity energy expenditure explain the between-individual variation in plasma leptin concentrations after adjusting for differences in body composition?
    Paul W Franks
    University of Cambridge, Department of Public Health and Primary Care, Cambridge, United Kingdom
    J Clin Endocrinol Metab 88:3258-63. 2003
    ..28, P = 0.005; women: beta = -0.23, P = 0.01; combined: beta = -0.26, P = 0.00008). These data suggest the existence in this population of an independent inverse association between PAEE and fasting plasma leptin level...
  54. doi request reprint Functional characterization of naturally occurring pathogenic mutations in the human leptin receptor
    Wendy Kimber
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, Cambridge CB2 0QQ, United Kingdom
    Endocrinology 149:6043-52. 2008
    ..Naturally occurring mutations associated with human obesity are valuable tools with which to explore structure/function relationships within the LR...
  55. pmc Pro-opiomelanocortin modulates the thermogenic and physical activity responses to high-fat feeding and markedly influences dietary fat preference
    Y C Loraine Tung
    Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Endocrinology 148:5331-8. 2007
    ..This includes a major influence, readily discernible even in heterozygote animals, on the dietary preference for fat...
  56. pmc Hypothalamic-specific manipulation of Fto, the ortholog of the human obesity gene FTO, affects food intake in rats
    Yi Chun Loraine Tung
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Treatment Centre, Addenbrooke s Hospital, Cambridge, United Kingdom
    PLoS ONE 5:e8771. 2010
    ..Importantly, this provide the first indication that selective alteration of FTO levels in the hypothalamus can influence food intake, a finding consistent with the reported effects of FTO alleles on appetite and food intake in man...
  57. pmc Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus
    Yi Chun Loraine Tung
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, Cambridge CB2 0QQ, United Kingdom
    J Neurosci 28:12419-26. 2008
    ..Thus, in addition to its effects on the expression of a broad range of neuropeptides, leptin may also exert more general influences on synaptic function in, and the bioenergetic state of, the PVN...
  58. ncbi request reprint Genetics of obesity in humans
    Sadaf Farooqi
    University Departments of Medicine and Clinical Biochemistry, Box 232, Addenbrooke s Hospital, Cambridge CB2 2QQ, United Kingdom
    Endocr Rev 27:710-18. 2006
    ....
  59. pmc A comparative study of the central effects of specific proopiomelancortin (POMC)-derived melanocortin peptides on food intake and body weight in pomc null mice
    Y C Loraine Tung
    Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge CB2 2QR, United Kingdom
    Endocrinology 147:5940-7. 2006
    ..Although other melanocortins can reduce food intake in the short-term, only alpha-MSH can reduce the excess fat and lean mass found in Pomc-/- mice, mediated largely through an effect on food intake...
  60. pmc Peripheral administration of the N-terminal pro-opiomelanocortin fragment 1-28 to Pomc-/- mice reduces food intake and weight but does not affect adrenal growth or corticosterone production
    Anthony P Coll
    Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge CB2 2XY, UK
    J Endocrinol 190:515-25. 2006
    ..In a mouse model which lacks all endogenous POMC peptides, s.c. treatment with synthetic 1-28 POMC alone can reduce food intake and body weight, but has no impact upon adrenal growth or steroidogenesis...
  61. ncbi request reprint Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA
    Miguel Lopez
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QR, U K
    Diabetes 55:1327-36. 2006
    ..The finding that TMX can modulate appetite through alterations in FAS expression and malonyl-CoA levels suggests a link between hypothalamic sex steroid receptors, fatty acid metabolism, and feeding behavior...
  62. ncbi request reprint Decreased brown adipocyte recruitment and thermogenic capacity in mice with impaired peroxisome proliferator-activated receptor (P465L PPARgamma) function
    Sarah L Gray
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QR, United Kingdom
    Endocrinology 147:5708-14. 2006
    ....
  63. ncbi request reprint Proopiomelanocortin and energy balance: insights from human and murine genetics
    Anthony P Coll
    University Departments of Medicine and Clinical Biochemistry, Cambridge Institute of Medical Research, Addenbrooke s Hospital, Cambridge, United Kingdom CB2 2QQ
    J Clin Endocrinol Metab 89:2557-62. 2004
    ....
  64. doi request reprint Kinetic analysis of FTO (fat mass and obesity-associated) reveals that it is unlikely to function as a sensor for 2-oxoglutarate
    Marcella Ma
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke s Hospital, UK
    Biochem J 444:183-7. 2012
    ..The K(m) of 2.88 μM is up to 10-fold lower than the estimated intracellular concentrations of 2-OG, rendering it unlikely that FTO functions as a sensor for 2-OG levels...
  65. ncbi request reprint Minireview: human obesity-lessons from monogenic disorders
    Stephen O'Rahilly
    University Department of Medicine, Cambridge Institute of Medical Research, Addenbrooke s Hospital, Cambridge CB2 2QQ, United Kingdom
    Endocrinology 144:3757-64. 2003
    ....
  66. ncbi request reprint Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy
    William T Gibson
    University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, United Kingdom CB2 2XY
    J Clin Endocrinol Metab 89:4821-6. 2004
    ....
  67. pmc Distinct modulatory effects of satiety and sibutramine on brain responses to food images in humans: a double dissociation across hypothalamus, amygdala, and ventral striatum
    Paul C Fletcher
    Department of Psychiatry, University of Cambridge, GlaxoSmithKline Clinical Unit Cambridge, Addenbrooke s Centre for Clinical Investigations, Addenbrooke s Hospital, Cambridge CB2 2QQ, United Kingdom
    J Neurosci 30:14346-55. 2010
    ..Furthermore, they support a regionally specific effect on brain function through which sibutramine exerts its clinical effect...
  68. ncbi request reprint Tyrosine agonists reverse the molecular defects associated with dominant-negative mutations in human peroxisome proliferator-activated receptor gamma
    Maura Agostini
    Department of Medicine, University of Cambridge, Addenbrooke s Hospital, United Kingdom
    Endocrinology 145:1527-38. 2004
    ..Having shown that rosiglitazone is of variable and limited efficacy in these subjects, we suggest that TAs may represent a more rational therapeutic approach...
  69. pmc Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies
    Robert K Semple
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK
    Diabetes 56:1712-7. 2007
    ....
  70. ncbi request reprint Mutational analysis of the serotonin receptor 5HT2c in severe early-onset human obesity
    William T Gibson
    Department of Clinical Biochemistry and Cambridge Institute for Medical Research, Addenbrooke s Hospital, UK
    Can J Physiol Pharmacol 82:426-9. 2004
    ..9%, respectively. In conclusion, mutations in 5HT2c are unlikely to be a common cause of severe early-onset human obesity. The identification of several novel polymorphisms at this locus may aid future genetic epidemiological studies...
  71. pmc Mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy
    Alison Sleigh
    Wolfson Brain Imaging Centre, Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom
    J Clin Endocrinol Metab 97:E438-42. 2012
    ..The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle...
  72. pmc Genetic defects in human pericentrin are associated with severe insulin resistance and diabetes
    Isabel Huang-Doran
    Institute of Metabolic Science, Addenbrooke s Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK
    Diabetes 60:925-35. 2011
    ..We thus set out to determine the prevalence of diabetes and insulin resistance among patients with PCNT defects and examined the effects of pericentrin depletion on insulin action using 3T3-L1 adipocytes as a model system...
  73. ncbi request reprint Mutations in the human melanocortin-4 receptor gene associated with severe familial obesity disrupts receptor function through multiple molecular mechanisms
    Giles S H Yeo
    Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke s Hospital, Cambridge CB2 2XY, UK
    Hum Mol Genet 12:561-74. 2003
    ....
  74. ncbi request reprint Lamin expression in human adipose cells in relation to anatomical site and differentiation state
    Christopher J Lelliott
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom
    J Clin Endocrinol Metab 87:728-34. 2002
    ..Nonetheless, these studies provide new information regarding the expression of lamin isoforms in normal human adipose cells, which will inform future studies of the molecular pathogenesis of FPLD...
  75. ncbi request reprint Role of the POZ zinc finger transcription factor FBI-1 in human and murine adipogenesis
    Matthias Laudes
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 2QR, United Kingdom
    J Biol Chem 279:11711-8. 2004
    ....
  76. pmc Leptin regulates striatal regions and human eating behavior
    I Sadaf Farooqi
    University Department of Medicine and Department of Clinical Biochemistry, Addenbrooke s Hospital, University of Cambridge, Cambridge CB2 2QQ, UK
    Science 317:1355. 2007
    ....
  77. doi request reprint Complement abnormalities in acquired lipodystrophy revisited
    David B Savage
    Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke s Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom
    J Clin Endocrinol Metab 94:10-6. 2009
    ....
  78. doi request reprint Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity
    I Sadaf Farooqi
    University of Cambridge Metabolic Research Laboratories, Addenbrooke s Hospital, Cambridge, UK
    Nat Clin Pract Endocrinol Metab 4:569-77. 2008
    ..The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin-melanocortin pathway, which is critical for the regulation of food intake and body weight...
  79. pmc Recent advances in the genetics of severe childhood obesity
    I S Farooqi
    University Departments of Medicine and Clinical Biochemistry, Box 157, Addenbrooke s Hospital, Cambridge CB2 2QQ, UK
    Arch Dis Child 83:31-4. 2000
    ..The discovery of these genetic defects has biological and clinical implications which are greater than the rarity of the individual diseases might suggest...
  80. doi request reprint Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion
    Carlos E Martinelli
    Department of Pediatrics, Hospital das Clinicas, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
    J Clin Endocrinol Metab 96:E181-8. 2011
    ..Melanocortin receptor 4 (MC4R) deficiency is characterized by increased linear growth greater than expected for the degree of obesity...
  81. doi request reprint Leptin: a pivotal regulator of human energy homeostasis
    I Sadaf Farooqi
    University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Box 289, Addenbrooke s Hospital, Cambridge CB2 0QQ, United Kingdom
    Am J Clin Nutr 89:980S-984S. 2009
    ....
  82. pmc Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis
    Robert K Semple
    Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrooke s Hospital, Cambridge, United Kingdom
    J Clin Invest 119:315-22. 2009
    ....
  83. ncbi request reprint Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism
    R K Semple
    Department of Clinical Biochemistry, Addenbrooke s Hospital, Cambridge CB2 2QR, United Kingdom
    J Clin Endocrinol Metab 90:1849-55. 2005
    ..These novel mutations provide further evidence that human HH may be caused by loss-of-function mutations in GPR54...
  84. ncbi request reprint Studies of the SIM1 gene in relation to human obesity and obesity-related traits
    C C C Hung
    University Department of Medicine, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, UK
    Int J Obes (Lond) 31:429-34. 2007
    ..SIM1-deficient mice have a hypocellular PVN and are severely obese with increased food intake...
  85. ncbi request reprint Uncoupling protein 3 genetic variants in human obesity: the c-55t promoter polymorphism is negatively correlated with body mass index in a UK Caucasian population
    D J Halsall
    University Department of Clinical Biochemistry, Addenbrooke s Hospital, Cambridge, UK
    Int J Obes Relat Metab Disord 25:472-7. 2001
    ..To investigate whether genetic variation at the UCP3 locus contributes to human obesity...
  86. ncbi request reprint Monogenic human obesity syndromes
    I S Farooqi
    Department of Medicine, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK
    Prog Brain Res 153:119-25. 2006
    ....
  87. ncbi request reprint Partial leptin deficiency and human adiposity
    I S Farooqi
    University Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
    Nature 414:34-5. 2001
    ....
  88. ncbi request reprint Genetic variation in the corticotrophin-releasing factor receptors: identification of single-nucleotide polymorphisms and association studies with obesity in UK Caucasians
    B G Challis
    University Departments of Medicine and Clinical Biochemistry, Addenbrooke s Hospital, Cambridge, UK
    Int J Obes Relat Metab Disord 28:442-6. 2004
    ..To investigate whether genetic variation at the loci encoding the corticotropin-releasing factor receptors-1 and -2 (CRF-R1 and CRF-R2) contributes to human obesity...
  89. ncbi request reprint Monogenic human obesity syndromes
    I S Farooqi
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Cambridge CB2 2QQ, United Kingdom
    Recent Prog Horm Res 59:409-24. 2004
    ....
  90. ncbi request reprint Congenital leptin deficiency is associated with severe early-onset obesity in humans
    C T Montague
    University of Cambridge, Department of Medicine, UK
    Nature 387:903-8. 1997
    ..The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans...
  91. ncbi request reprint The role of melanocortin signalling in the control of body weight: evidence from human and murine genetic models
    G S Yeo
    Departments of Medicine and Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke s Hospital, University of Cambridge, Cambridge, UK
    QJM 93:7-14. 2000
    ..The development of pharmacological agonists acting on, or mimicking, the hypothalamic melanocortinergic pathway may provide exciting opportunities for the therapy of human obesity...
  92. ncbi request reprint Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity
    J Gray
    Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke s Hospital, Cambridge, UK
    Int J Obes (Lond) 31:359-64. 2007
    ..We have now undertaken a more detailed analysis of the in vitro functional consequences of the mutations identified: I98V, P660L, T821A and Y722C...
  93. ncbi request reprint The CART gene and human obesity: mutational analysis and population genetics
    B G Challis
    University Department of Medicine, Addenbrooke s Hospital, Cambridge, UK
    Diabetes 49:872-5. 2000
    ....
  94. pmc Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene
    Juliette Gray
    University Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke s Hospital, Cambridge, CB2 2XY, U K
    Diabetes 55:3366-71. 2006
    ..These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior...
  95. ncbi request reprint WNT10B mutations in human obesity
    C Christodoulides
    Department of Clinical Biochemistry, University of Cambridge, Addenbrooke s Hospital, Box 232, Cambridge, CB2 2QQ, UK
    Diabetologia 49:678-84. 2006
    ..In order to determine whether mutations in WNT10B contribute to human obesity, we screened two independent populations of obese subjects for mutations in this gene...
  96. ncbi request reprint Genetic factors in human obesity
    I S Farooqi
    University of Cambridge, Cambridge Institute for Medical Research and the Department of Clinical Biochemistry, Cambridge, UK
    Obes Rev 8:37-40. 2007