Seipin oligomers can interact directly with AGPAT2 and lipin 1, physically scaffolding critical regulators of adipogenesis

This work was supported by a Merit Scholarship from the Islamic Development Bank (to M.M.U.T.), The Agency for Science, Technology and Research, Singapore (A*STAR) (M.F.M.S), the Medical Research Council (MRC) [NIRG GO800203 and Research Grant MR/L002620/1 (to J.J.R.), Program GrantG09000554 (to S.O.R)], The Wellcome Trust [078986/Z/06/Z (to S.O.R.)], the MRC Centre for Obesity and Related Metabolic Disorders (MRC-CORD) [GO600717] and the NIHR Comprehensive Biomedical Research Centre [CG50826].Peer reviewedPublisher PD

Analysis of naturally occurring mutations in the human lipodystrophy protein seipin reveals multiple potential pathogenic mechanisms

Peer reviewedPublisher PD

Fat mass and obesity-related (FTO) shuttles between the nucleus and cytoplasm.

SNPs (single nucleotide polymorphisms) on a chromosome 16 locus encompassing FTO, as well as IRX3, 5, 6, FTM and FTL are robustly associated with human obesity. FTO catalyses the Fe(II)- and 2OG-dependent demethylation of RNA and is an AA (amino acid) sensor that couples AA levels to mTORC1 (mammalian target of rapamycin complex 1) signalling, thereby playing a key role in regulating growth and translation. However, the cellular compartment in which FTO primarily resides to perform its biochemical role is unclear. Here, we undertake live cell imaging of GFP (green fluorescent protein)-FTO, and demonstrate that FTO resides in both the nucleus and cytoplasm. We show using 'FLIP' (fluorescence loss in photobleaching) that a mobile FTO fraction shuttles between both compartments. We performed a proteomic study and identified XPO2 (Exportin 2), one of a family of proteins that mediates the shuttling of proteins between the nucleus and the cytoplasm, as a binding partner of FTO. Finally, using deletion studies, we show that the N-terminus of FTO is required for its ability to shuttle between the nucleus and cytoplasm. In conclusion, FTO is present in both the nucleus and cytoplasm, with a mobile fraction that shuttles between both cellular compartments, possibly by interaction with XPO2.This is the final published version. It first appeared at http://www.bioscirep.org/bsr/034/bsr034e144.htm

Human Obesity: A Heritable Neurobehavioral Disorder That Is Highly Sensitive to Environmental Conditions

The recent increase in the worldwide prevalenceof obesity has understandably focused attentionon the environmental determinants of this epi-demic. Whereas identifying the relative contribu-tions of the factors underlying this recent trend is critical, a comprehensive understanding of the causes of obesity will need to explain why, even in high-risk populations, many people remain lean. Contemporary studies indicate that the heritability of adiposity remains high, even in the face of a strongly obesogenic environment. Whereas the role of inheritance has long been appreciated, only re-cently have we begun to develop a genuine understanding of the critical role of specific molecules in sensing the state of nutrient storage and regulating food intake and energy expenditure. Notably, a number of single gene disorders resulting in human obesity have been uncovered and, strikingly, all of these defects impair the central control of food intake. Early indications are that commo

FTO is necessary for the induction of leptin resistance by high-fat feeding.

OBJECTIVE: Loss of function FTO mutations significantly impact body composition in humans and mice, with Fto-deficient mice reported to resist the development of obesity in response to a high-fat diet (HFD). We aimed to further explore the interactions between FTO and HFD and determine if FTO can influence the adverse metabolic consequence of HFD. METHODS: We studied mice deficient in FTO in two well validated models of leptin resistance (HFD feeding and central palmitate injection) to determine how Fto genotype may influence the action of leptin. Using transcriptomic analysis of hypothalamic tissue to identify relevant pathways affected by the loss of Fto, we combined data from co-immunoprecipitation, yeast 2-hybrid and luciferase reporter assays to identify mechanisms through which FTO can influence the development of leptin resistant states. RESULTS: Mice deficient in Fto significantly increased their fat mass in response to HFD. Fto (+/-) and Fto (-/-) mice remained sensitive to the anorexigenic effects of leptin, both after exposure to a HFD or after acute central application of palmitate. Genes encoding components of the NFкB signalling pathway were down-regulated in the hypothalami of Fto-deficient mice following a HFD. When this pathway was reactivated in Fto-deficient mice with a single low central dose of TNFα, the mice became less sensitive to the effect of leptin. We identified a transcriptional coactivator of NFкB, TRIP4, as a binding partner of FTO and a molecule that is required for TRIP4 dependent transactivation of NFкB. CONCLUSIONS: Our study demonstrates that, independent of body weight, Fto influences the metabolic outcomes of a HFD through alteration of hypothalamic NFкB signalling. This supports the notion that pharmacological modulation of FTO activity might have the potential for therapeutic benefit in improving leptin sensitivity, in a manner that is influenced by the nutritional environment.The authors thank Roger Cox (MRC Harwell) for kindly providing us with the Fto-deficient mouse strain. This study was supported by the Medical Research Council (MRC) Metabolic Disease Unit (MRC_MC_UU_12012/1), EU FP7- FOOD- 266408 Full4Health and the Helmholtz Alliance ICEMED.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S2212877815000241#

Truncation of POC1A associated with short stature and extreme insulin resistance.

We describe a female proband with primordial dwarfism, skeletal dysplasia, facial dysmorphism, extreme dyslipidaemic insulin resistance and fatty liver associated with a novel homozygous frameshift mutation in POC1A, predicted to affect two of the three protein products of the gene. POC1A encodes a protein associated with centrioles throughout the cell cycle and implicated in both mitotic spindle and primary ciliary function. Three homozygous mutations affecting all isoforms of POC1A have recently been implicated in a similar syndrome of primordial dwarfism, although no detailed metabolic phenotypes were described. Primary cells from the proband we describe exhibited increased centrosome amplification and multipolar spindle formation during mitosis, but showed normal DNA content, arguing against mitotic skipping, cleavage failure or cell fusion. Despite evidence of increased DNA damage in cells with supernumerary centrosomes, no aneuploidy was detected. Extensive centrosome clustering both at mitotic spindles and in primary cilia mitigated the consequences of centrosome amplification, and primary ciliary formation was normal. Although further metabolic studies of patients with POC1A mutations are warranted, we suggest that POC1A may be added to ALMS1 and PCNT as examples of centrosomal or pericentriolar proteins whose dysfunction leads to extreme dyslipidaemic insulin resistance. Further investigation of links between these molecular defects and adipose tissue dysfunction is likely to yield insights into mechanisms of adipose tissue maintenance and regeneration that are critical to metabolic health.This work was supported by the Wellcome Trust [grant numbers WT098498, WT098051,WT095515, and WT091310]; the Medical Research Council [MRC_MC_UU_12012/5]; the United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Bioscientifica via http://dx.doi.org/10.1530/JME-15-009

Harveian Oration 2016: Some observations on the causes and consequences of obesity.

The excitement of clinical science was first made apparent to me through the somewhat theatrical medium of the medical ‘grand round’. In the 1980s, at both Hammersmith Hospital and Oxford, where I undertook postgraduate training, the format was in its heyday. A junior doctor would present the history and clinical and investigative features of a patient with a puzzling illness. This was followed by a scholarly dissection of the key issues by the presenter, after which the chair and a distinguished audience would subject the arguments to forensic dissection. Not infrequently, ongoing research in laboratories within the hospital had actually generated new knowledge directly relevant to the patient and the audience would hear of these discoveries for the first time. It was a powerful vehicle for conveying the thrill of clinical science. It was, moreover, a form of discourse that William Harvey would have understood well. In endowing this lecture, he stipulated that the orator should ‘exhort the Fellows and Members of this College to search and study out the secrets of nature by way of experiment’.1 In the 17th century, non-invasive forms of medical science were limited in scope. Anatomical dissection was the principal tool and, of necessity, the only patients who could be subjected to that form of examination were those no longer alive. In his notes for the Lumleian Lectures, Harvey reminded himself ‘Not to praise or dispraise other anatomists, for all did well, and there was some excuse even for those who are in error’.1 That kind exhortation might bring a wry smile to those who remember the Hammersmith Hospital rounds of the 1980s, where impassioned clashes between the giants of medicine gathered there made the atmosphere more ‘Grand Guignol’ than ‘grand round’

Development, factor structure and application of the Dog Obesity Risk and Appetite (DORA) questionnaire.

Background. Dogs are compelling models in which to study obesity since the condition shares many characteristics between humans and dogs. Differences in eating behaviour are recognised to contribute to obesity susceptibility in other species but this has not been systematically studied in dogs. Aim. To develop and validate an owner-reported measure of canine eating behaviour and owner or dog related factors which can alter the development of obesity. Further, to then test variation in food-motivation in dogs and its association with obesity and owner management. Methods. Owner interviews, a literature review and existing human appetite scales were used to identify relevant topics and generate items for the questionnaire. Following a pilot phase, a 75 item online questionnaire was distributed via social media. Responses from 302 dog/owner dyads were analysed and factor structure and descriptive statistics calculated. Results were compared with descriptions of dog behaviour and management from a subset of respondents during semi-structured interviews. The optimum questions were disseminated as a 34 item final questionnaire completed by 213 owners, with a subset of respondents repeating the questionnaire 3 weeks later to assess test-retest reliability. Results. Analysis of responses to the final questionnaire relating to 213 dog/owner dyads showed a coherent factor structure and good test-retest reliability. There were three dog factors (food responsiveness and satiety, lack of selectivity, Interest in food), four owner factors (owner motivation to control dog weight, owner intervention to control dog weight, restriction of human food, exercise taken) and two dog health factors (signs of gastrointestinal disease, current poor health). Eating behaviour differed between individuals and between breed groups. High scores on dog factors (high food-motivation) and low scores on owner factors (less rigorous control of diet/exercise) were associated with obesity. Owners of more highly food-motivated dogs exerted more control over their dogs' food intake than those of less food-motivated dogs. Conclusions. The DORA questionnaire is a reliable and informative owner-reported measure of canine eating behaviour and health and management factors which can be associated with obesity development. The tool will be applicable to study of the canine obesity model and to clinical veterinarians. Results revealed eating behaviour to be similarly associated with obesity as exercise and owners giving titbits

Severe obesity and diabetes insipidus in a patient with PCSK1 deficiency.

Non-synonymous mutations affecting both alleles of PCSK1 (proprotein convertase 1/3) are associated with obesity and impaired prohormone processing. We report a proband who was compound heterozygous for a maternally inherited frameshift mutation and a paternally inherited 474kb deletion that encompasses PCSK1, representing a novel genetic mechanism underlying this phenotype. Although pro-vasopressin is not a known physiological substrate of PCSK1, the development of central diabetes insipidus in this proband suggests that PCSK1 deficiency can be associated with impaired osmoregulation.ISF and SOR were supported by the Wellcome Trust, the MRC Centre for Obesity and Related Disorders and the UK NIHR Cambridge Biomedical Research Centre.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S1096719213001145#

GDF15: A Hormone Conveying Somatic Distress to the Brain.

GDF15 has recently gained scientific and translational prominence with the discovery that its receptor is a GFRAL-RET heterodimer of which GFRAL is expressed solely in the hindbrain. Activation of this receptor results in reduced food intake and loss of body weight and is perceived and recalled by animals as aversive. This information encourages a revised interpretation of the large body of previous research on the protein. GDF15 can be secreted by a wide variety of cell types in response to a broad range of stressors. We propose that central sensing of GDF15 via GFRAL-RET activation results in behaviors that facilitate the reduction of exposure to a noxious stimulus. The human trophoblast appears to have hijacked this signal, producing large amounts of GDF15 from early pregnancy. We speculate that this encourages avoidance of potential teratogens in pregnancy. Circulating GDF15 levels are elevated in a range of human disease states, including various forms of cachexia, and GDF15-GFRAL antagonism is emerging as a therapeutic strategy for anorexia/cachexia syndromes. Metformin elevates circulating GDF15 chronically in humans and the weight loss caused by this drug appears to be dependent on the rise in GDF15. This supports the concept that chronic activation of the GDF15-GFRAL axis has efficacy as an antiobesity agent. In this review, we examine the science of GDF15 since its identification in 1997 with our interpretation of this body of work now being assisted by a clear understanding of its highly selective central site of action