Obesity and Metabolism

Our work

Our ongoing research programmes combine basic science with studies in healthy human volunteers and obese and type 2 diabetic patients. Human studies are underpinned by detailed phenotyping including gut hormone profiling and functional brain imaging coupled with genetics, with the aim of developing personalised therapeutic strategies.

Our expertise lies in cell culture, generation of transgenic mice, energy and glucose homeostasis phenotyping of mouse models, immunohistochemistry, in situ hybridisation studies, microscopy, RNA and DNA isolation/analysis and quantification, ELISAs, radioimmunoassay, functional magnetic resonance imaging, phenotyping of healthy volunteers and patients.

Investigating the Mechanisms Underlying Bariatric Surgery

Bariatric surgery is the most effective treatment option for obesity resulting in substantial and durable weight loss, with a reduction in mortality and obesity-related co-morbidities.

Obesity is the primary risk factor for type 2 diabetes mellitus (T2DM) which is characterised by insufficient insulin secretion and insulin resistance. Proximal gastric bypass surgery (PGBP) and sleeve gastrectomy (SG) reduce excess body weight by up to 80%. Also, most individuals with T2DM that undergo PGBP show immediate improved glycaemic control following surgery before significant weight loss. Whilst many therapeutic regimens aim to modulate glucose concentrations to prevent end-organ damage, bariatric surgery seems to be the only treatment modality with the potential to induce complete resolution of T2DM. However, the mechanisms underlying this process remain elusive.

Understanding how these surgical procedures induce sustained weight loss and resolution of T2DM holds the key to the development of more directed, less invasive therapies and is one of our key research focuses. There is increasing evidence that the reduced appetite and improved glucose homeostasis observed in the early postoperative period after certain types of bariatric surgery are due to alterations in circulating gut hormones.

To gain a further understanding of these processes, we undertake studies on patients undergoing bariatric surgery at UCLH. We have also established a mouse model of bariatric surgery to enable us to gain further mechanistic insights.

Gaining Insights into how the Gut-Brain Axis Regulates Feeding Behaviour

Complex interrelated neuronal circuits have developed in the mammalian brain to regulate many aspects of feeding behaviour.  An increased understanding of how peripheral energy signals act upon these circuits to regulate food intake is essential for the effective treatment of the current obesity crisis. We have shown that the gut hormone peptide YY (PYY) regulates feeding behaviour in rodents and humans and identified that the neuropeptide Y2 receptor is crucial for the anorectic effects of PYY.

By generating mice-lacking PYY, we have shown that this hormone plays a crucial role in the regulation of body weight. Moreover, we have shown that infusion of PYY reduces food intake in obese human subjects. Using fMRI in healthy male volunteers we have shown that PYY modulates neuronal activity within both homeostatic (hypothalamic and brainstem) and hedonic (orbitofrontal cortex) brain regions. 

More recently, again using fMRI, we have shown that the neural response to visual food images within key brain appetite and reward brain regions in markedly altered in normal-weight subjects carrying two copies of the obesity-risk FTO gene variant.

Gut Hormones and Exercise

In collaboration with Dr David Stensel's group at Loughborough University, we have undertaken a series of studies that have investigated the effects of different types of exercise (aerobic or resistance) and exercise intensity on appetite and gut hormones.

We have found that aerobic exercise causes the greatest suppression of hunger and leads to a more favourable profile of appetite-regulating hormones (lower ghrelin and higher PYY). In addition, we have shown that high-intensity intermittent exercise produces greater appetite suppression with concomitant higher circulating PYY3-36 concentrations than energy-matched continuous exercise. 

We are now investigating the mechanisms underlying these gut hormone changes.

Insights from Genetics

Genome-wide association studies have identified several obesity SNPs. However, the mechanisms by which these SNPs mediate their effects on body weight are unclear. We are undertaking detailed phenotype/genotype studies in normal-weight subjects and obese patients to gain insights into the biology of obesity risk.

Collaborative projects

UCL / UCLH

• Dr M. Banks (Gastroenterology)
• Professor J. Deanfield (Institute of Cardiovascular Science)
• Professor R. Dolan (Wellcome Trust Center for Neuroimaging, UCL)
• Professor N. Donos (Eastman Dental)
• Mr P. Hardiman (Women's Health)
• Professor H. Montgomery (Medicine)
• Dr A Jones (Institute of Cardiovascular Science)
• Professor R. Viner (Adolescent Health)
• Professor J. Wardle (Epidemiology and Public Health)

External

• PI on MRC International Mouse Phenotyping Consortium (Cambridge, Oxford and Imperial College),
• Dr D. Stensel (Loughborough, UK)
• Professor F. Gribble (Cambridge. UK)
• Professor S.C. Williams (King's College London, UK)
• Professor D.J. Withers (Imperial College, UK), 
• Professor M. McCarthy (Oxford, UK), Dr F. Andreelli (Cochin Institute, Paris)
• Professor F. Santini (Pisa University)
• Dr R. Magi (Estonia University)
• Professor J. Bruening (University of Cologne)
• Dr A. Leiter (University of Massachusetts)
• Dr C. Lindgren (Broad Institute of MIT and Harvard, Boston USA)
• Dr H. Iwakura (Kyoto University Hospital, Japan).

Our experts

Publications

1. Norton BC, Telese A, Papaefthymiou A, Aslam N, Makaronidis J, Murray C, Haidry R (2023). Metabolic and Bariatric Endoscopy: A Mini-Review. Life. 2023; 13(9):1905.
2. Mok J, Adeleke MO, Brown A, Magee CG, Firman C, Makahamadze C, Jassil FC ... Batterham RL, Makaronidis J (2023). Safety and Efficacy of Liraglutide, 3.0 mg, Once Daily vs Placebo in Patients With Poor Weight Loss Following Metabolic Surgery: The BARI-OPTIMISE Randomized Clinical Trial. JAMA Surg. 2023 Jul 26:e232930.
3. Jassil FC, Carnemolla A, Kingett H, Doyle J, Kirk A, Lewis N, Montagut G, Marvasti P, Boniface D, Brown A, et al. (2023). Impact of nutritional-behavioral and supervised exercise intervention following bariatric surgery: The BARI-LIFESTYLE randomized controlled trial. Obesity (Silver Spring). 2023 Aug;31(8):2031-2042.
4. Wingrove J, Makaronidis J, Magee C et al. (2023) Aberrant Olfactory Network Functional Connectivity in People with Olfactory Dysfunction Following COVID-19 Infection: An Exploratory, Observational Study. E Clinical Medicine
5. Makaronidis JM, Pucci A, Adamo M, Jenkinson A, Elkalaawy M, Batterham RL (2022). Impact of sleeve gastrectomy compared to Roux-en-Y gastric bypass upon hedonic hunger and the relationship to post-operative weight loss. Intern Emerg Med. 2022 Oct;17(7):2031-2038.
6. Brown A, Flint SW, Batterham RL. (2022). Pervasiveness, impact, and implications of weight stigma. eClinicalMedicine, 47.
7. Makaronidis J, Firman C, Magee CG, et al (2021). Distorted chemosensory perception and female sex associate with persistent smell and/or taste loss in people with SARS-CoV-2 antibodies: a community-based cohort study investigating clinical course and resolution of acute smell and/or taste loss in people with and without SARS-CoV-2 antibodies in London, UK. BMC Infect Dis 21, 221 (2021) Feb 25;21(1):221.
8. Busetto L, Bettini S, Makaronidis J, Roberts CA, Halford JCG, Batterham RL (2021). Mechanisms of weight regain. Eur J Intern Med. 2021 Nov;93:3-7.
9. Brown A, Flint SW, Kalea AZ, O'Kane M, Williams S, Batterham RL (2021). Negative impact of the first COVID-19 lockdown upon health-related behaviours and psychological wellbeing in people living with severe and complex obesity in the UK. EClinicalMedicine. 2021 Apr;34:100796. Epub 2021 Mar 18.
10. Makaronidis J, Mok J, Balogun N, Magee CG, Omar RZ, Carnemolla A, Batterham RL (2020). Seroprevalence of SARS-CoV-2 antibodies in people with an acute loss in their sense of smell and/or taste in a community-based population in London, UK: An observational cohort study. PLoS Med. 2020 Oct 1;17(10):e1003358.
11. Makaronidis JM, Batterham RL (2019). The role of gut hormones in the pathogenesis and management of obesity. Current Opinion in Physiology, 2019, Vol. 12, 1-11.
12. Makaronidis JM, Batterham RL. Obesity, body weight regulation and the brain: insights from fMRI. Br J Radiol. 2018 Sep;91(1089):20170910.
13. Pucci A, Tymoszuk U, Cheung WH, Makaronidis JM, Scholes S, et al (2017). Type 2 diabetes remission 2 years post Roux-en-Y gastric bypass and sleeve gastrectomy: the role of the weight loss and comparison of DiaRem and DiaBetter scores. Diabet Med. 2018 Mar;35(3):360-367.
14. Busetto L, Dicker D, Azran C, Batterham RL, Farpour-Lambert N, Fried M, Hjelmesaeth J, Kinzl J, Leitner DR, Makaronidis JM, et al (2017). Practical Recommendations of the Obesity Management Task Force of the European Association for the Study of Obesity for the Post-Bariatric Surgery Medical Management. Obesity facts. 2017;10(6):597-632.
15. Makaronidis JM, Batterham RL (2016). Potential Mechanisms Mediating Sustained Weight Loss Following Roux-en-Y Gastric Bypass and Sleeve Gastrectomy. Endocrinol Metab Clin North Am. 2016 Sep;45(3):539-52.
16. Makaronidis JM, Neilson S, Cheung WH, Tymoszuk U, et al (2016). Reported appetite, taste and smell changes following Roux-en-Y gastric bypass and sleeve gastrectomy: Effect of gender, type 2 diabetes and relationship to post-operative weight loss. Appetite. 2016 Dec 1;107:93-105.

Funding and Partnerships

Charities

• Obesity Empowerment Network
• Academic of Nutrition Science

Collaborators

• University of Leeds
• University of Aberdeen
• Leeds Beckett University
• University of Liverpool
• Robert Gordon University
• King College London
• University of Oxford
• University of Leicester 
• Aston University 
• University of Cambridge
• Homerton University Hospital
• Queen Mary University London