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. 2016 Dec;16(6):551-564.
doi: 10.7861/clinmedicine.16-6-551.

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

Stephen O'Rahilly  1
Affiliations

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

Stephen O'Rahilly. Clin Med (Lond). 2016 Dec.
No abstract available

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Figures

Fig 1.
Fig 1.
Venus of Willendorf. Palaeolithic carving in oolitic limestone from about 25,000 BCE. Wellcome Library, London.
Fig 2.
Fig 2.
Child with congenital leptin deficiency before (aged 3 years) and after (aged 7 years) leptin therapy. Modified with permission from the Annual Review of Medicine 2005, volume 56, pp 443–58. © by Annual Reviews, www.annualreviews.org
Fig 3.
Fig 3.
Coordination of the control of triglyceride breakdown on the surface of the adipocyte fat droplet in the fasting and fed state in a healthy individual (A) and in a patient with a mutation disrupting the C-terminus of perilipin 1 (B). In the fasting state, perilipin 1 (P1), a protein that sits on the surface of the triglyceride droplet of the fat cell, is phosphorylated near its C-terminus. This prevents it from binding CGI58 and allows the latter to bind and activate adipocyte triglyceride lipase (ATGL), the enzyme that initiates triglyceride breakdown. The diglycerides formed by this reaction are broken down by hormone-sensitive lipase (HSL), the active phosphorylated form of which binds to perilipin 1 when the latter is phosphorylated at a residue close to its N-terminus. Monoglyceride lipase (MGL) is constitutively active. Thus, in the fasting state, the fat cell efficiently releases abundant free fatty acid into the systemic circulation for use by other organs. In the fed state, perilipin 1 is dephosphorylated and binds tightly to CGI58, preventing it from interacting with and activating ATGL; HSL does not interact with dephosphorylated perilipin 1 and thus the process of adipocyte lipolysis is efficiently shut down in the fed state while triglyceride synthesis is activated, with free fatty acids derived from triglycerides delivered to the fat tissue in lipoproteins generated in the gut and the liver, with lesser amounts coming from re-esterification and from de novo lipogenesis in fat. Patients with mutations that disrupt the C-terminal phosphorylation site of a single copy of their perilipin 1 protein have a syndrome characterised by all the features of the metabolic syndrome in the face of a diminished, but not absent, fat cell mass. This occurs because the mutant C-terminal tail of perilipin 1 is unable to bind CGI58 so, even in the fed state, ATGL remains at the lipid droplet surface and active; thus, free fatty acids are generated from the adipocyte irrespective of the nutritional state. That disruption of lipid droplet triglyceride regulation is sufficient, alone, to result in every feature of the metabolic syndrome. ATGL = adipocyte triglyceride lipase; C = C-terminus of perilipin 1; DG = diglyceride; FA = fatty acid; FFA = free fatty acid; HSL = hormone-sensitive lipase; LPL = lipoprotein lipase; MG = monoglyceride; MGL = monoglyceride lipase; N = N-terminus of perilipin 1; P1 = perilipin 1; TG = triglyceride
Fig 4.
Fig 4.
The ‘soggy bathroom carpet’ model of over-nutrition-related metabolic disease. A – In health, chronic energy intake (the flow through the tap) is matched by energy expenditure (the flow through the open plughole) such that there is a moderate but healthy amount of excess energy stored (the water rises, but does not overflow the bathtub). B – In an individual with marked obesity that has led to diabetes, the energy inflow chronically exceeds the energy outflow such that the amount of stored energy exceeds the capacity to safely store it and excess nutrients flow elsewhere, causing damage (the soggy carpet). C – In individuals with a limited ability to expand adipose tissue storage capacity (a smaller bathtub), even a small excess of energy intake over expenditure will lead to energy being misdirected (overflowing the bathtub) and to adverse metabolic outcomes including fatty liver, insulin resistance and diabetes.
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