Dulloo, Abdul G.

Montani, Jean-Pierre

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Invited commentaryObesity in Parkinson’s disease patients on electrotherapy: collateral damage,adiposity rebound or secular trends?Whether obesity should be considered as a disease is debatable, butit is undeniable that it provokes the development of debilitatingdiseases that include type 2 diabetes, CVD and some forms ofcancer. Consequently, emerging evidence that functional brain sur-gery for alleviating the clinical symptoms of Parkinson’s disease –by electrode implantation for deep-brain stimulation – results in arelatively high prevalence of overweight and even obesity maysound like jumping from the frying pan into the fire.First described in 1817 by James Parkinson in his essay on ‘Theshaking palsy’, Parkinson’s disease is a chronic and progressiveneurological disorder characterised by rigidity of the limbs, trunkand face, tremor when awake and resting, abnormal body postureand difficulties in initiating voluntary motor activity (akinesia).The clinical manifestation of the syndrome usually begins in thefifth decade of life, and results from degeneration and prematuredeath of brain cells that produce dopamine, a neurochemical thatplays an important role in the control of motor functions (Samiiet al. 2004). Hailed as one of the miracles of modern medicineafter its introduction to treat Parkinson’s disease in the late1960s, levodopa, which is taken up by dopaminergic neuronswhere it is made into dopamine, is particularly effective in restor-ing the ability to initiate movement. But after an initial satisfactoryresponse to levodopa (or to dopamine agonists), many patientsdevelop motor fluctuations that are difficult to control. They alter-nate between a state of severe parkinsonism (the ‘drug-off’ periodwhen the medication is not working) and a state of improved mobi-lity (often accompanied by dyskinesia) during the ‘drug-on’ periodwhen the medication is working. The patients become susceptibleto malnutrition, since both the disease symptoms and the medi-cation side-effects (nausea, vomiting) can limit food intake,while involuntary movements and the development of musclerigidity can lead to marked elevations in ‘resting’ energy expendi-ture (Markus et al. 1992). Parkinson’s disease patients are fourtimes more likely to report weight loss exceeding 4 kg thanmatched control subjects, and to have lower BMI, triceps skinfoldthickness and percentage body fat, which correlate significantlywith weight change and the stage of the disease (Beyer et al.1995). Despite the fact that these complications become increas-ingly common and disabling with longer durations of the diseaseand of exposure to levodopa, the latter remains the most potentantiparkinson drug and is the backbone of treatment throughoutmuch of the disease course.Attempts to alleviate the ‘levodopa syndrome’ have led to aresurgence of surgical treatments centred upon the ablation ofdeep brain structures. Indeed, before levodopa, thalamotomywas found to reduce contralateral tremor, while pallidotomy vari-ably improved motor symptoms in Parkinson’s disease. Therenewed interest in functional brain surgery has now shifted tohigh-frequency stimulation of deep-brain targets, which causesless irreversible brain trauma than ablative surgery. Among theanatomical targets for such brain electrotherapy, bilateral stimu-lation of the internal segment of the globus pallidus or the subtha-lamic nucleus has emerged as being particularly effective atrelieving motor symptoms. These procedures provide consider-able clinical benefits, in terms of both improvement in primarysymptoms (tremor, bradykinesia and muscle rigidity) and resol-ution of side-effects of chronic pharmacological treatment (dyski-nesia). It also permits a 50 % or more reduction in the levodopadosage required for satisfactory symptom control (Lang, 2003;Samii et al. 2004). Although poorly documented, there are alsoreports that many patients show modest weight gain (Moro et al.1999; Gironell et al. 2002; Romito et al. 2003), which is thoughtto be consequential to the improvements in involuntary move-ments and in mood, and hence in the normalisation of energyintake and energy expenditure to the pre-disease (and pre-weight loss) level. Whether deep-brain stimulation of the bilateralsubthalamic nucleus (referred to as STN-DBS) is superior to bilat-eral globus pallidus stimulation in patients with Parkinson’s dis-ease is unclear, but recent reports that excessive weight gain iscommon in patients treated by STN-DBS are likely to fuel furtherthe on-going debate about the best stimulation target for thisdisorder.Indeed, two independent retrospective studies – one from Italy(Barichella et al. 2003) and the other from France (Macia et al.2004) – that have evaluated body weight changes in STN-DBS-treated Parkinson’s patients up to 14 months after electrode implan-tation report an average weight gain of 9·3 kg and 9·7 kg, respect-ively. Comparison of the distribution of BMI before and after theprocedure indicates a clear shift from underweight and normalweight towards overweight and even obesity. It is clear that expla-nations as to why more than 25 % of patients gained between 10and 16 kg in a year, and weighed more than they ever had in theirlifetime, go well beyond the normalisation of body weight to pre-disease levels. Given the close correlation observed betweenchanges in motor scores and body weight gain assessed at 3months and a year after surgical intervention, the question arisesas to whether STN-DBS intervention – perhaps throughinterference with nearby hypothalamic areas involved in controllingappetite and energy expenditure – could underlie this apparent dys-regulation of body weight. However, weight overshooting basedupon ‘collateral damage’ from STN-DBS therapy seems unlikely,judging from a follow-up of the French study published in a previousissue of this journal (Perlemoine et al. 2005). In the follow-up, rest-ing energy expenditure, substrate oxidation and daily energy intakewere compared in STN-DBS-treated patients, in non-operatedpatients (awaiting surgery) and in a group of healthy controls.Although 1 year after STN-DBS electrotherapy the operatedpatients showed lower resting energy expenditure as well as lowerBritish Journal of Nutrition (2005), 93, 417–419 DOI: 10.1079/BJN20041337q The Authors 2005https:/www.cambridge.org/core/terms. https://doi.org/10.1079/BJN20041337Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 30 May 2017 at 20:22:11, subject to the Cambridge Core terms of use, available atfat and protein oxidation than the non-operated patients, no signifi-cant differences were found in resting metabolism or in energyintake between STN-DBS-treated patients and healthy controls.Thus, STN-DBS therapy did not seem to perturb energy intakeand energy expenditure beyond levels found in healthy individuals,and excessive weight gain following such electrotherapy wouldseem to be related to changes in the cardinal manifestations of Par-kinson’s disease itself, rather than to secondary changes resultingfrom the surgery.A more likely scenario, at least among STN-DBS-treatedpatients who may have lost a substantial amount of weightduring the course of the disease, is that the improvements inmotor functions in the months immediately following electrother-apy led to an unmasking of autoregulatory mechanisms that nor-mally operate to restore body fat and fat-free mass throughincreases in hunger and/or through adaptive reductions inenergy expenditure (Dulloo et al. 1997; Dulloo & Jacquet,1998). These mechanisms are thought to underlie the phenom-enon of disproportionate rate of fat recovery and fat overshooting,i.e. ‘adiposity rebound’, which has been observed during follow-up studies of famine victims of World War II, and documented inlongitudinal studies of experimental starvation and re-feeding inman (see Table 1).In their classic Minnesota Experiment of semi-starvation and re-feeding, Keys et al. (1950) described this phenomenon as ‘post-star-vation obesity’. It has, in more recent years, been traced to the asym-metry in body fat and fat-free mass recovery consequential tomechanisms that suppressed thermogenesis specifically for acceler-ating recovery of fat mass, and not fat-free mass (Dulloo et al. 1997;Dulloo & Jacquet, 1998; Weyer et al. 2000). Thus, in Parkinson’spatients who may have lost a considerable amount of body fatduring the course of the disease, the efficacy of the STN-DBS in nor-malising motor functions may, paradoxically, have disinhibitedintrinsic mechanisms of adiposity rebound that underlie the syn-drome of ‘post-starvation obesity’. These same mechanisms, in par-ticular those that suppress thermogenesis in favour of acceleratingspecifically fat recovery (or catch-up fat), also confer to the phaseof weight recovery its particularly high sensitivity to the develop-ment of hyperinsulinaemia and insulin resistance (Dulloo et al.2002; Crescenzo et al. 2003), thereby putting the patient at riskfor obesity and type 2 diabetes.Finally, secular changes in body weight and adiposity might alsobe relevant in explaining weight overshooting in the STN-DBS-treated Parkinson’s patients, given disease duration of 10–15years before the start of electrotherapy. During this period, anincrease in the prevalence of overweight and obesity of similarmagnitude among the general population of the same age range(50–70 years) is not unusual. This ‘secular trend’ factor mayassume even greater significance given recent findings – fromtwo prospective epidemiological studies – that increased adiposityduring middle adulthood is associated with an elevated risk for Par-kinson’s disease later in life, notably 15–30 years later (Abbottet al. 2002; Chen et al. 2004). These epidemiological associationsbetween midlife adiposity and later Parkinson’s disease, whosecardinal signs are largely due to the loss of dopamine-producingneurons in the substantia nigra area in the brain, together with clini-cal observations that obesity is associated with depletion of striataldopamine D2 receptor availability (Wang et al. 2001), suggest thatnigrostriatal system disorders are associated with both Parkinson’sdisease and obesity (Abbott et al. 2002). It has also been proposedthat either obesity down-regulates dopamine D2 receptors, perhapsto compensate for increased dopamine concentration associatedwith overeating, or lower dopamine D2 receptor availability maylead to overeating and obesity. In either case, the lower dopamineD2 receptor availability may predispose those with a tendency tofatness to later risk for Parkinson’s disease (Chen et al. 2004). Inthis context, the efficacy of STN-DBS in normalising motor func-tions in some Parkinson’s disease patients some 10–20 years afterclinical diagnosis of the disease may also have allowed theirinherent predisposition to obesity to manifest itself.Whatever the exact explanations for weight overshooting inSTN-DBS-treated Parkinson’s disease patients, the subthalamicnucleus is likely to become a new centre of attraction for investi-gations towards understanding how body weight is regulated, andhow some individuals become more prone to obesity than others.Abdul G DullooJean-Pierre MontaniDepartment of Medicine/PhysiologyUniversity of FribourgChemin du Muse´e 51700 FribourgSwitzerlandemail: abdul.dulloo@unifr.chReferencesAbbott RD, Ross GW, White LR, Nelson JS, Masaki KH, Tanner CM,Curb JD, Blanchette PL, Popper JS & Petrovitch H (2002) Midlife adi-posity and the future risk of Parkinson’s disease. Neurology 59,1051–1057.Barichella M, Marczewska AM, Mariani C, Landi A, Vairo A & Pezzoli G(2003) Body weight gain in patients with Parkinson’s disease and deepbrain stimulation. Mov Disord 18, 1337–1340.Benedict FG (1907) The Influence of Inanition on Metabolism. CarnegieInstitute of Washington Publication, no. 77. Washington, DC: CarnegieInstitute of Washington.Benedict FG, Miles WR, Roth P & Smith HM (1919) Human Vitality andEfficiency under Prolonged Restricted Diet. Carnegie Institute ofWashington Publication, no. 280. Washington, DC: Carnegie Instituteof Washington.Beyer PL, Palarino MY, Michalek D, Busenbark K & Koller WC (1995)Weight change and body composition in patients with Parkinson’s dis-ease. J Am Diet Assoc 95, 979–983.Chen H, Zhang SM, Schwarzschild MA, Hernan MA, Willett WC &Ascherio A (2004) Obesity and the risk of Parkinson’s disease. Am JEpidemiol 159, 547–555.Crescenzo R, Samec S, Antic V, Rohner-Jeanrenaud F, Seydoux J, Mon-tani JP & Dulloo AG (2003) A role for suppressed thermogenesis favor-ing catch-up fat in the pathophysiology of catch-up growth. Diabetes52, 1090–1097.Table 1. Post-starvation weight overshooting in manStudyType of energydeprivation nWeightovershoot (kg)Benedict (1907) Total fast 5 2·7Benedict et al. (1919) Semi-starvation 11 3·1Keys et al. (1950) Semi-starvation 12 3·6*Martin & Demole (1973) Food rationing 700 6·5* Excess weight was accounted for by fat, measured by hydrostatic weighing.A. G. Dulloo and J.-P. Montani418https:/www.cambridge.org/core/terms. https://doi.org/10.1079/BJN20041337Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 30 May 2017 at 20:22:11, subject to the Cambridge Core terms of use, available atDulloo AG & Jacquet J (1998) Adaptive reduction in basal metabolic ratein response to food deprivation in humans: a role for feedback signalsfrom fat stores. Am J Clin Nutr 68, 599–606.Dulloo AG, Jacquet J & Girardier L (1997) Poststarvation hyperphagiaand body fat overshooting in humans: a role for feedback signalsfrom lean and fat tissues. Am J Clin Nutr 65, 717–723.Dulloo AG, Jacquet J & Montani JP (2002) Pathways from weight fluctu-ations to metabolic diseases: focus on maladaptive thermogenesisduring catch-up fat. Int J Obes Relat Metab Disord 26, Suppl. 2,S46–S57.Gironell A, Pascual-Sedano B, Otermin P & Kulisevsky J (2002) Weightgain after functional surgery for Parkinson’s disease. Neurologia 17,310–316.Keys A, Brozek J, Henschel A, Mickelsen O & Taylor HL (1950) TheBiology of Human Starvation. Minneapolis, MN: University ofMinnesota Press.Lang AE (2003) Subthalamic stimulation for Parkinson’s disease – livingbetter electrically? N Engl J Med 349, 1888–1891.Macia F, Perlemoine C, Coman I, Guehl D, Burbaud P, Cuny E, Gin H,Rigalleau V & Tison F (2004) Parkinson’s disease patients with bilat-eral subthalamic deep brain stimulation gain weight. Mov Disord 19,206–212.Markus HS, Cox M & Tomkins AM (1992) Raised resting energy expen-diture in Parkinson’s disease and its relationship to muscle rigidity. ClinSci 83, 199–204.Martin E & Demole M (1973) Une expe´rience scientifique d’alimentationcontrole´e: le rationnement en Suisse pendant la deuxie`me guerremondiale (A scientific experiment of controlled food intake: food ration-ing in Switzerland during World War II). In Re´gulation de l’EquilibreEnerge´tique chez l’Homme, vol. 1, pp. 185–193 [M Apfelbaum,editor]. Paris: Masson.Moro E, Scerrati M, Romito LM, Roselli R, Tonali P & Albanese A(1999) Chronic subthalamic nucleus stimulation reduces medicationrequirements in Parkinson’s disease. Neurology 53, 85–90.Perlemoine C, Macia F, Tison F, Coman I, Guehl D, Burbaud P, Ciny E,Baillet L, Gin H & Rigalleau V (2005) Effects of subthalamicnucleus deep brain stimulation and levodopa on energy productionrate and substrate oxidation in Parkinson’s disease. Br J Nutr 93,191–198.Romito LM, Scerrati M, Contarino MF, Iacoangeli M, Bentivoglio AR &Albanese A (2003) Bilateral high frequency subthalamic stimulation inParkinson’s disease: long-term neurological follow-up. J Neurosurg Sci47, 119–128.Samii A, Nutt JG & Ransom BR (2004) Parkinson’s disease. Lancet 363,1783–1793.Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W,Netusil N & Fowler JS (2001) Brain dopamine and obesity. Lancet357, 354–357.Weyer C, Walford RL, Harper IT, Milner M, MacCallum T, Tataranni PA& Ravussin E (2000) Energy metabolism after 2 y of energy restriction:the biosphere 2 experiment. Am J Clin Nutr 72, 946–953.Invited commentary 419https:/www.cambridge.org/core/terms. https://doi.org/10.1079/BJN20041337Downloaded from https:/www.cambridge.org/core. University of Basel Library, on 30 May 2017 at 20:22:11, subject to the Cambridge Core terms of use, available at

Obesity in Parkinson's disease patients on electrotherapy: collateral damage, adiposity rebound or secular trends?

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