Publications by authors named "I Sadaf Farooqi"

214 Publications

Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.

PLoS Biol 2021 Nov 8;19(11):e3001255. Epub 2021 Nov 8.

The Gurdon Institute and Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.

The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.
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http://dx.doi.org/10.1371/journal.pbio.3001255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575313PMC
November 2021

Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with delayed gastric emptying.

Clin Endocrinol (Oxf) 2021 Oct 25. Epub 2021 Oct 25.

Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Hills Road, Cambridge, UK.

Objective: People who are severely obese due to melanocortin-4 receptor (MC4R) deficiency experience hyperphagia and impaired fullness after a meal (satiety). Meal-induced satiety is influenced by hormones, such as peptide-YY (PYY), which are released by enteroendocrine cells upon nutrient delivery to the small intestine.

Design: We investigated whether gastric emptying and PYY levels are altered in MC4R deficiency.

Methods: Gastric emptying was measured with a gastric scintigraphy protocol using technetium-99m ( Tc )-Tin Colloid for 3.5 h in individuals with loss of function MC4R variants and a control group of similar age and weight. In a separate study, we measured plasma PYY levels before and at multiple time points after three standardised meals given to individuals with MC4R deficiency and controls. Fasting PYY (basal secretion) and postprandial PYY levels were measured and the area under the curve and inter-meal peak were calculated.

Results: We found that gastric emptying time was significantly delayed and percentage meal retention increased in individuals with MC4R deficiency compared to obese controls. In addition, fasting and mean PYY secretion throughout the day were decreased in MC4R deficiency, whereas postprandial PYY secretion was unaltered.

Conclusion: Delayed gastric emptying and reduced basal PYY secretion may contribute to impaired satiety in people with obesity due to MC4R deficiency.
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http://dx.doi.org/10.1111/cen.14615DOI Listing
October 2021

Obesity-Associated Mutations and the Melanocortin Pathway.

N Engl J Med 2021 10 6;385(17):1581-1592. Epub 2021 Oct 6.

From the University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge (E.M.O., J.M.K., F.T., E.H., R.A., A.P., R.B., N.W., V.A., J.M., I.S.F.), the Exeter Centre of Excellence for Diabetes Research, University of Exeter Medical School, Exeter (I.B.), Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham (D.J., M.K.), Broomfield Hospital, Chelmsford (S.L.), Hull University Teaching Hospitals NHS Trust, Hull (S.G.), East and North Hertfordshire NHS Trust Lister Hospital, Stevenage (C.M.), County Durham and Darlington NHS Foundation Trust, Darlington (P.P.), Nottingham Children's Hospital, Nottingham (T.R.), University Hospitals Dorset NHS Foundation Trust, Poole (A.M.), Great Ormond Street Hospital for Children NHS Foundation Trust, London (L.C.W.), the Translational and Clinical Research Institute, Newcastle University, and Great North Children's Hospital, Royal Victoria Infirmary, Newcastle upon Tyne (T.C.), University Hospitals Bristol and Weston NHS Foundation Trust, Bristol (E.C.C.), and the Division of Developmental Biology and Medicine, University of Manchester, Manchester (P.C.) - all in the United Kingdom.

Background: encodes the Gα (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism).

Methods: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 mutation carriers. We investigated whether the effect of mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays.

Results: Almost all mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have mutations (3.9±2.6 mIU per liter; P = 0.004).

Conclusions: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).
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http://dx.doi.org/10.1056/NEJMoa2103329DOI Listing
October 2021

Murine neuronatin deficiency is associated with a hypervariable food intake and bimodal obesity.

Sci Rep 2021 09 2;11(1):17571. Epub 2021 Sep 2.

MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0SL, UK.

Neuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat mice developing obesity. In response to both a 45% high fat diet and exposure to thermoneutrality (30 °C) Nnat deficient mice maintained the hypervariable body weight phenotype. Within a calorimetry system, food intake in Nnat mice was hypervariable, with some mice consuming more than twice the intake seen in wild type littermates. A hyperphagic response was also seen in Nnat mice in a second, non-home cage environment. An expected correlation between body weight and energy expenditure was seen, but corrections for the effects of positive energy balance and body weight greatly diminished the effect of neuronatin deficiency on energy expenditure. Male and female Nnat mice displayed subtle distinctions in the degree of variance body weight phenotype and food intake and further sexual dimorphism was reflected in different patterns of hypothalamic gene expression in Nnat mice. Loss of the imprinted gene Nnat is associated with a highly variable food intake, with the impact of this phenotype varying between genetically identical individuals.
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http://dx.doi.org/10.1038/s41598-021-96278-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413370PMC
September 2021

Monogenic human obesity syndromes.

Authors:
I Sadaf Farooqi

Handb Clin Neurol 2021 ;181:301-310

Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom. Electronic address:

Neural circuits in the hypothalamus play a key role in the regulation of human energy homeostasis. A critical circuit involves leptin-responsive neurons in the hypothalamic arcuate nucleus (the infundibular nucleus in humans) expressing the appetite-suppressing neuropeptide proopiomelanocortin (POMC) and the appetite-stimulating Agouti-related peptide. In the fed state, the POMC-derived melanocortin peptide α-melanocyte-stimulating hormone stimulates melanocortin-4 receptors (MC4Rs) expressed on second-order neurons in the paraventricular nucleus of the hypothalamus (PVN). Agonism of MC4R leads to reduced food intake and increased energy expenditure. Disruption of this hypothalamic circuit by inherited mutations in the genes encoding leptin, the leptin receptor, POMC, and MC4R can lead to severe obesity in humans. The characterization of these and closely related genetic obesity syndromes has informed our understanding of the neural pathways by which leptin regulates energy balance, neuroendocrine function, and the autonomic nervous system. A broader understanding of these neural and molecular mechanisms has paved the way for effective mechanism-based therapies for patients whose severe obesity is driven by disruption of these pathways.
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http://dx.doi.org/10.1016/B978-0-12-820683-6.00022-1DOI Listing
July 2021
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