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: neil.docherty@ucd.ie



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