Which Organ is Responsible for the Pathogenesis of Obesity?

A Melvin, CW le Roux, NG Docherty 

Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine University College Dublin

Obesity is associated with significant complications and healthcare costs, but our ability to treat obesity has been limited by our understanding of its pathogenesis. We surveyed diabetologists and obesity related health care professionals asking them which organ they believed to be responsible for the pathogenesis of obesity. Participants favoured a central nervous system (CNS) aetiology. The response echoes evidence from genome wide association studies identifying a link between obesity and CNS loci. Our most successful obesity therapies involve the manipulation of subcortical area of the brain involved in energy balance. Future success in the management of obesity will be determined by our ability to define the pathogenesis of the disease in individual cases, moving from a “one size fits all” to more focused interventions

The prevalence of obesity as defined by World Health Organisation (WHO) criteria of a body mass index greater than 30kg/m2 is estimated at 25.6% in Ireland1. The mechanical impact of excess body weight and its relationship to the development of medical conditions such as arthritis and obstructive sleep apnoea is apparent. However, arguably the most serious and costly consequences of obesity are those that are mediated through the role of visceral adipose tissue in the metabolic syndrome2. We have been far more successful at managing obesity related complications than treating obesity itself. To stem the incidence of complications, we must target the primary disease as this may ultimately have a greater impact on health outcomes. However poor understanding of the organ system responsible for obesity has been a limiting step thus far. We set out to determine the opinion of healthcare professionals with an interest in diabetes and obesity as to the organ responsible for the pathogenesis of obesity.


At an international meeting attended by diabetes and obesity-related healthcare professionals, a lecture was delivered entitled ‘Focused weight management strategies-Building on the pathophysiology”.  All delegates in attendance were asked to participate in a survey prior to commencement of the lecture. Each attendee was presented with the question “Which organ/tissue do you believe is most important in the pathogenesis of obesity?” Delegates were instructed to choose from five responses: A) Adipose tissue, B) The liver, C) The subcortical areas of the brain involved in vital function, D) The cortical areas of the brain involved in willpower, or E) The gut. The five organ systems included in the survey were chosen to reflect those most represented in current experimental pathology literature. Answers were submitted electronically using tablets allowing immediate data capture, each participant was permitted to submit one answer.

Two hundred and seventy-five medical doctors attended the lecture and 92% responded to the survey. Eighty-nine (32.4%) delegates answered cortical areas of the brain involved in will power and 86 (31.2%) subcortical areas of the brain involved in vital function. Of the remaining respondents 38 (13.8%) chose adipose tissue, 32 (11.6%) the gut and 8 (2.9%), believed the liver to be the main organ involved in obesity pathogenesis.

Diabetologists and obesity-related healthcare professionals favoured the central nervous system (CNS) as being of primacy in the pathogenesis of obesity. Opinion was divided between this being a disorder of willpower (cortical areas), or one of vital function (subcortical areas). The majority of the respondents’ feedback is consistent with genome wide association work identifying the vast majority of loci associated with obesity linked to the central nervous system3. Understanding of whether cortical or subcortical areas of the brain are responsible for the pathogenesis of obesity may be fundamental in determining our therapeutic strategies. Obesity being a disorder of willpower has been the prevailing view for many years and has resulted in significant discrimination against people who are obese4,5, but has also made lifestyle based treatments the dominant therapeutic strategy. With very few exceptions overall lifestyle approaches that address the cortical areas of the brain with education, diet approaches, exercise prescription and behavioural therapy have resulted in unsatisfactory weight loss over long term follow-up6. In contrast, therapeutic approaches that target the subcortical areas of the brain such as medications that bind receptors in the hypothalamus or surgery that generates hormonal and neural signals that alter activity in the subcortical areas of the brain result in 10-25% weight loss in the long term7,8.

While respondents overwhelmingly favoured a CNS cause, it is important not to discount the influence of peripheral signals on the CNS loci regulating weight, as our ability to manipulate these signals remains a mainstay in obesity therapy. Scientific breakthroughs both in understanding the aetiology and pathogenesis of obesity as well as the understanding of the mechanisms of successful interventions are allowing new insights to develop. We have adopted a “one size fits all” approach to managing obesity, but identifying the organ responsible for the pathogenesis of obesity may allow for the development of a far more focused approach to help combat the epidemic.


Correspondence: Dr. NG Docherty

Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin
Email: [email protected]



1. WHO. World Health Organisation Global Health Observatory Data; Overweight and Obesity. 2014.

2. Vincent RP, Ashrafian H, le Roux CW. Mechanisms of Disease: the role of gastrointestinal hormones in appetite and obesity. Nat Clin Pract Gastroenterol Hepatol. 2008;5:268-77.

3. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich ML, Yang J, Croteau-Chonka DC, Esko T, Fall T, Ferreira T,Gustafsson S, Kutalik Z, Luan J, Mägi R, Randall JC, Winkler TW, Wood AR, Workalemahu T, Faul JD, Smith JA, Hua Zhao J, Zhao W, Chen J, Fehrmann R,Hedman ÅK, Karjalainen J, Schmidt EM, Absher D, Amin N, Anderson D, Beekman M, Bolton JL, Bragg-Gresham JL, Buyske S, Demirkan A, Deng G, Ehret GB,Feenstra B, Feitosa MF, Fischer K, Goel A, Gong J, Jackson AU, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Mangino M, Mateo Leach I, Medina-Gomez C, Medland SE, Nalls MA, Palmer CD, Pasko D, Pechlivanis S, Peters MJ, Prokopenko I, Shungin D, Stančáková A, Strawbridge RJ, Ju Sung Y, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet-Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Isaacs A, Albrecht E, Ärnlöv J, Arscott GM,Attwood AP, Bandinelli S, Barrett A, Bas IN, Bellis C, Bennett AJ, Berne C, Blagieva R, Blüher M, Böhringer S, Bonnycastle LL, Böttcher Y, Boyd HA,Bruinenberg M, Caspersen IH, Ida Chen YD, Clarke R, Daw EW, de Craen AJ, Delgado G, Dimitriou M, Doney AS, Eklund N, Estrada K, Eury E, Folkersen L,Fraser RM, Garcia ME, Geller F, Giedraitis V, Gigante B, Go AS, Golay A, Goodall AH, Gordon SD, Gorski M, Grabe HJ, Grallert H, Grammer TB, Gräßler J,Grönberg H, Groves CJ, Gusto G, Haessler J, Hall P, Haller T, Hallmans G, Hartman CA, Hassinen M, Hayward C, Heard-Costa NL, Helmer Q, Hengstenberg C,Holmen O, Hottenga JJ, James AL, Jeff JM, Johansson Å, Jolley J, Juliusdottir T, Kinnunen L, Koenig W, Koskenvuo M, Kratzer W, Laitinen J, Lamina C,Leander K, Lee NR, Lichtner P, Lind L, Lindström J, Sin Lo K, Lobbens S, Lorbeer R, Lu Y, Mach F, Magnusson PK, Mahajan A, McArdle WL, McLachlan S,Menni C, Merger S, Mihailov E, Milani L, Moayyeri A, Monda KL, Morken MA, Mulas A, Müller G, Müller-Nurasyid M, Musk AW, Nagaraja R, Nöthen MM, Nolte IM, Pilz S, Rayner NW, Renstrom F, Rettig R, Ried JS, Ripke S, Robertson NR, Rose LM, Sanna S, Scharnagl H, Scholtens S, Schumacher FR, Scott WR,Seufferlein T, Shi J, Vernon Smith A, Smolonska J, Stanton AV, Steinthorsdottir V, Stirrups K, Stringham HM, Sundström J, Swertz MA, Swift AJ, Syvänen AC, Tan ST, Tayo BO, Thorand B, Thorleifsson G, Tyrer JP, Uh HW, Vandenput L, Verhulst FC, Vermeulen SH, Verweij N, Vonk JM, Waite LL, Warren HR, Waterworth D,Weedon MN, Wilkens LR, Willenborg C, Wilsgaard T, Wojczynski MK, Wong A, Wright AF, Zhang Q; LifeLines Cohort Study, Brennan EP, Choi M, Dastani Z,Drong AW, Eriksson P, Franco-Cereceda A, Gådin JR, Gharavi AG, Goddard ME, Handsaker RE, Huang J, Karpe F, Kathiresan S, Keildson S, Kiryluk K, Kubo M, Lee JY, Liang L, Lifton RP, Ma B, McCarroll SA, McKnight AJ, Min JL, Moffatt MF, Montgomery GW, Murabito JM, Nicholson G, Nyholt DR, Okada Y, Perry JR,Dorajoo R, Reinmaa E, Salem RM, Sandholm N, Scott RA, Stolk L, Takahashi A, Tanaka T, Van’t Hooft FM, Vinkhuyzen AA, Westra HJ, Zheng W, Zondervan KT;ADIPOGen Consortium; AGEN-BMI Working Group; CARDIOGRAMplusC4D Consortium; CKDGen Consortium; GLGC; ICBP; MAGIC Investigators; MuTHER Consortium; MIGen Consortium; PAGE Consortium; ReproGen Consortium; GENIE Consortium; International Endogene Consortium, Heath AC, Arveiler D,Bakker SJ, Beilby J, Bergman RN, Blangero J, Bovet P, Campbell H, Caulfield MJ, Cesana G, Chakravarti A, Chasman DI, Chines PS, Collins FS, Crawford DC,Cupples LA, Cusi D, Danesh J, de Faire U, den Ruijter HM, Dominiczak AF, Erbel R, Erdmann J, Eriksson JG, Farrall M, Felix SB, Ferrannini E, Ferrières J, Ford I, Forouhi NG, Forrester T, Franco OH, Gansevoort RT, Gejman PV, Gieger C, Gottesman O, Gudnason V, Gyllensten U, Hall AS, Harris TB, Hattersley AT, Hicks AA, Hindorff LA, Hingorani AD, Hofman A, Homuth G, Hovingh GK, Humphries SE, Hunt SC, Hyppönen E, Illig T, Jacobs KB, Jarvelin MR, Jöckel KH, Johansen B, Jousilahti P, Jukema JW, Jula AM, Kaprio J, Kastelein JJ, Keinanen-Kiukaanniemi SM, Kiemeney LA, Knekt P, Kooner JS, Kooperberg C, Kovacs P, Kraja AT,Kumari M, Kuusisto J, Lakka TA, Langenberg C, Le Marchand L, Lehtimäki T, Lyssenko V, Männistö S, Marette A, Matise TC, McKenzie CA, McKnight B, Moll FL, Morris AD, Morris AP, Murray JC, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Madden PA, Pasterkamp G, Peden JF, Peters A, Postma DS, Pramstaller PP,Price JF, Qi L, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ridker PM, Rioux JD, Ritchie MD, Rudan I, Salomaa V, Samani NJ, Saramies J, Sarzynski MA,Schunkert H, Schwarz PE, Sever P, Shuldiner AR, Sinisalo J, Stolk RP, Strauch K, Tönjes A, Trégouët DA, Tremblay A, Tremoli E, Virtamo J, Vohl MC, Völker U,Waeber G, Willemsen G, Witteman JC, Zillikens MC, Adair LS, Amouyel P, Asselbergs FW, Assimes TL, Bochud M, Boehm BO, Boerwinkle E, Bornstein SR,Bottinger EP, Bouchard C, Cauchi S, Chambers JC, Chanock SJ, Cooper RS, de Bakker PI, Dedoussis G, Ferrucci L, Franks PW, Froguel P, Groop LC, Haiman CA, Hamsten A, Hui J, Hunter DJ, Hveem K, Kaplan RC, Kivimaki M, Kuh D, Laakso M, Liu Y, Martin NG, März W, Melbye M, Metspalu A, Moebus S, Munroe PB,Njølstad I, Oostra BA, Palmer CN, Pedersen NL, Perola M, Pérusse L, Peters U, Power C, Quertermous T, Rauramaa R, Rivadeneira F, Saaristo TE, Saleheen D, Sattar N, Schadt EE, Schlessinger D, Slagboom PE, Snieder H, Spector TD, Thorsteinsdottir U, Stumvoll M, Tuomilehto J, Uitterlinden AG, Uusitupa M, van der Harst P, Walker M, Wallaschofski H, Wareham NJ, Watkins H, Weir DR, Wichmann HE, Wilson JF, Zanen P, Borecki IB, Deloukas P, Fox CS, Heid IM,O’Connell JR, Strachan DP, Stefansson K, van Duijn CM, Abecasis GR, Franke L, Frayling TM, McCarthy MI, Visscher PM, Scherag A, Willer CJ, Boehnke M,Mohlke KL, Lindgren CM, Beckmann JS, Barroso I, North KE, Ingelsson E, Hirschhorn JN, Loos RJ, Speliotes EK., Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197-206.

4. Hatzenbuehler ML, Keyes KM, Hasin DS. Associations between perceived weight discrimination and the prevalence of psychiatric disorders in the general population. Obesity (Silver Spring).2009;17:2033-9.

5. Frederick DA, Saguy AC, Sandhu G, Mann T. Effects of competing news media frames of weight on antifat stigma, beliefs about weight and support for obesity-related public policies. Int J Obes(Lond). 2015.

6. Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan CM, Espeland MA, Evans M, Foreyt JP,Ghazarian S, Gregg EW, Harrison B, Hazuda HP, Hill JO, Horton ES, Hubbard VS, Jakicic JM, Jeffery RW, Johnson KC, Kahn SE, Kitabchi AE, Knowler WC,Lewis CE, Maschak-Carey BJ, Montez MG, Murillo A, Nathan DM, Patricio J, Peters A, Pi-Sunyer X, Pownall H, Reboussin D, Regensteiner JG, Rickman AD,Ryan DH, Safford M, Wadden TA, Wagenknecht LE, West DS, Williamson DF, Yanovski SZ. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med.2013;369:145-54.

7. Pi-Sunyer X, Astrup A, Fujioka K., Greenway F, Halpern A, Krempf M, Lau, DCW, Carel W. le Roux CW, Ortiz RV, Jensen CB, Wilding JPJ. A Randomized, Controlled Trial of 3.0mg of Liraglutide in Weight Management. N Engl J Med. 2015;373:11-22.

8. Goldstone AP , Miras AD , Scholtz S , Jackson S , Neff KJ , Pénicaud L , Geoghegan J , Chhina N , Durighel G , Bell JD , Meillon S , le Roux CW . Link between increased satiety gut hormones and reduced food reward following gastric bypass surgery for obesity.J Clin Endocrinol Metab. 2015:jc20152665.