Search Results
You are looking at 1 - 5 of 5 items for
- Author: Stephen O'Rahilly x
- Refine by access: All content x
Search for other papers by I Sadaf Farooqi in
Google Scholar
PubMed
Search for other papers by Stephen O'Rahilly in
Google Scholar
PubMed
The discovery of leptin has provided a robust framework upon which our current understanding of the mechanisms involved in energy homeostasis has been built. In this review, we describe how the identification of humans with mutations in the genes encoding leptin and the leptin receptor and the characterisation of the associated clinical phenotypes have provided insights into the role of leptin-responsive pathways in the regulation of eating behaviour, intermediary metabolism and the onset of puberty. Importantly, administration of recombinant human leptin in leptin deficiency represents the first mechanistically based targeted therapy for obesity and has provided immense clinical benefits for the patients concerned. In subsequent years, we and others have shown that human obesity can result from a multiplicity of defects in the pathways downstream of leptin signalling within the brain.
Search for other papers by Isabel Huang-Doran in
Google Scholar
PubMed
Search for other papers by Alison Sleigh in
Google Scholar
PubMed
Search for other papers by Justin J Rochford in
Google Scholar
PubMed
Search for other papers by Stephen O'Rahilly in
Google Scholar
PubMed
Search for other papers by David B Savage in
Google Scholar
PubMed
Obesity, insulin resistance and their attendant complications are among the leading causes of morbidity and premature mortality today, yet we are only in the early stages of understanding the molecular pathogenesis of these aberrant phenotypes. A powerful approach has been the study of rare patients with monogenic syndromes that manifest as extreme phenotypes. For example, there are striking similarities between the biochemical and clinical profiles of individuals with excess fat (obesity) and those with an abnormal paucity of fat (lipodystrophy), including severe insulin resistance, dyslipidaemia, hepatic steatosis and features of hyperandrogenism. Rare lipodystrophy patients therefore provide a tractable genetically defined model for the study of a prevalent human disease phenotype. Indeed, as we review herein, detailed study of these syndromes is beginning to yield valuable insights into the molecular genetics underlying different forms of lipodystrophy, the essential components of normal adipose tissue development and the mechanisms by which disturbances in adipose tissue function can lead to almost all the features of the metabolic syndrome.
Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
Search for other papers by Zoi Michailidou in
Google Scholar
PubMed
Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
Search for other papers by Anthony P Coll in
Google Scholar
PubMed
Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
Search for other papers by Christopher J Kenyon in
Google Scholar
PubMed
Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
Search for other papers by Nicholas M Morton in
Google Scholar
PubMed
Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
Search for other papers by Stephen O’Rahilly in
Google Scholar
PubMed
Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
Search for other papers by Jonathan R Seckl in
Google Scholar
PubMed
Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK
Search for other papers by Karen E Chapman in
Google Scholar
PubMed
Proopiomelanocortin (POMC) deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigate against insulin resistance, hyperphagia and fat accretion in Pomc −/−mice. Upon exogenous glucocorticoid replacement, corticosterone-supplemented (CORT) Pomc −/− mice show exaggerated responses, including excessive fat accumulation, hyperleptinaemia and insulin resistance. To investigate the peripheral mechanisms underlying this glucocorticoid hypersensitivity, we examined the expression levels of key determinants and targets of glucocorticoid action in adipose tissue and liver. Despite lower basal expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11β-HSD1 mRNA levels was more pronounced in adipose tissues of Pomc −/−mice. Similarly, CORT treatment increased lipoprotein lipase mRNA levels in all fat depots in Pomc −/− mice, consistent with exaggerated fat accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal fat of Pomc −/− mice but were corrected by CORT in the latter depot. In liver, CORT increased phosphoenolpyruvate carboxykinase mRNA levels specifically in Pomc −/− mice, consistent with their insulin-resistant phenotype. Furthermore, CORT induced hypertension in Pomc −/−mice, independently of adipose or liver renin–angiotensin system activation. These data suggest that CORT-inducible 11β-HSD1 expression in fat contributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver.
Search for other papers by Sumit Bhattacharyya in
Google Scholar
PubMed
Search for other papers by Jian’an Luan in
Google Scholar
PubMed
Search for other papers by I Sadaf Farooqi in
Google Scholar
PubMed
Search for other papers by Julia Keogh in
Google Scholar
PubMed
Search for other papers by Carl Montague in
Google Scholar
PubMed
Search for other papers by John Brennand in
Google Scholar
PubMed
Search for other papers by Lynn Jorde in
Google Scholar
PubMed
Search for other papers by Nicholas J Wareham in
Google Scholar
PubMed
Search for other papers by Stephen O’Rahilly in
Google Scholar
PubMed
Central administration of neuromedin U (NMU) suppresses food intake acting through the NMU-2 receptor (NMU2R), which is expressed in the hypothalamus. We screened the NMU2R gene in 96 patients with severe early-onset obesity. A common variant haplotype was found (f-0.21). This common variant haplotype was unusual in nature, consisting of four non-contiguous missense changes in complete linkage disequilibrium, and across two separate exons. The variant haplotype resulted in four amino acid substitutions (S295T/F312L/P380L/ M385 V) and was present in several other Europid populations and in subjects of South Asian, East Asian and African American origin, but not in eleven African Pygmies. This variant haplotype was not associated with obesity or related traits in 500 subjects from a prospective population-based cohort.
In summary, we have identified two markedly different isoforms of the NMU-2 receptor, presumably arising through an ancient and complex mutational event; no genetic associations between this haplotype and obesity-related traits were, however, discerned. Further investigation of the pharmacogenomic consequences of NMU2R variation in humans is warranted.
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Anthony P Coll in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Martin Fassnacht in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Steffen Klammer in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Stephanie Hahner in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Dominik M Schulte in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Sarah Piper in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Y C Loraine Tung in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Benjamin G Challis in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Yacob Weinstein in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Bruno Allolio in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Stephen O’Rahilly in
Google Scholar
PubMed
Division of Endocrinology, Department of Internal Medicine I, University Hospital Würzburg 97080, Germany
Division of Endocrinology and Diabetes, Department of Internal Medicine II, Klinikum der Albert-Ludwigs-Universität Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany
Department of Microbiology and Immunology, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel
Search for other papers by Felix Beuschlein in
Google Scholar
PubMed
Pro-opiomelanocortin (POMC) is a polypeptide precursor that undergoes extensive processing to yield a range of peptides with biologically diverse functions. POMC-derived ACTH is vital for normal adrenal function and the melanocortin α-MSH plays a key role in appetite control and energy homeostasis. However, the roles of peptide fragments derived from the highly conserved N-terminal region of POMC are less well characterized. We have used mice with a null mutation in the Pomc gene (Pomc −/−) to determine the in vivo effects of synthetic N-terminal 1–28 POMC, which has been shown previously to possess adrenal mitogenic activity. 1–28 POMC (20 μg) given s.c. for 10 days had no effect on the adrenal cortex of Pomc −/− mice, with resultant cortical morphology and plasma corticosterone levels being indistinguishable from sham treatment. Concurrent administration of 1–28 POMC and 1–24 ACTH (30 μg/day) resulted in changes identical to 1–24 ACTH treatment alone, which consisted of upregulation of steroidogenic enzymes, elevation of corticosterone levels, hypertrophy of the zona fasciculate, and regression of the X-zone. However, treatment of corticosterone-depleted Pomc −/− mice with 1–28 POMC reduced cumulative food intake and total body weight. These anorexigenic effects were ameliorated when the peptide was administered to Pomc −/− mice with circulating corticosterone restored either to a low physiological level by corticosterone-supplemented drinking water (CORT) or to a supraphysiological level by concurrent 1–24 ACTH administration. Further, i.c.v. administration of 1–28 POMC to CORT-treated Pomc −/− mice had no effect on food intake or body weight. In wild-type mice, the effects of 1–28 POMC upon food intake and body weight were identical to sham treatment, but 1–28 POMC was able to ameliorate the hyperphagia induced by concurrent 1–24 ACTH treatment. 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.
