Mechanisms of Body Weight Gain in Patients With Parkinson's Disease After Subthalamic Stimulation

C. Montaurier; B. Morio; S. Bannier; P. Derost; P. Arnaud; M. Brandolini-Bunlon; C. Giraudet; Y. Boirie; F. Durif


Brain. 2007;130(7):1808-1818. 

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In the present study, we demonstrate that Parkinson's disease is associated with profound alterations in energy metabolism that are normalized after DBS-STN implantation while energy intake is maintained. Parkinsonian patients had gained an average 3 kg at 3 months post-surgery. However, there were significant inter-individual variations and gender-related differences in the quality of body weight gain. In men, around two-thirds of body weight gain was due to an increase in FFM while women gained only fat. The marked changes in EE observed in this study have important implications in terms of practical and clinical recommendations for reducing energy intake as well as for scheduling progressive physical training in the early days following brain surgery.

Body weight loss is often observed with Parkinson's disease. The 2-year prospective study conducted by Palhagen et al. (2005) showed a modest body weight loss before patients begin L-dopa treatment (–1.1 kg vs control) that becomes significant after 2 years of L-dopa therapy (–5.6 kg vs control). Conflicting results have been obtained regarding Parkinson's disease-induced changes in body composition. In the present study, most patients presented a low percentage fat mass and had to be matched to healthy active subjects. This is consistent with Palhagen et al. (2005), Beyer et al. (1995) and Revilla et al. (1988), although not with Petroni et al. (2003). Since body weight results from the balance between energy intake and EE, each component of the balance has to be monitored. Measurements in calorimetric chambers have demonstrated increased daily EE in treated Parkinsonian patients compared to healthy subjects matched for body composition and performing the same physical activity program. These alterations in energy metabolism would explain the body weight loss of L-dopa-treated patients if food intake is not sufficiently increased to match daily energy needs. Several hypotheses have been put forward to explain body weight loss in patients with Parkinson's disease, including a decrease in food intake caused by motor difficulties in eating (Andersson et al., 2001), reduced appetite secondary to depressive symptoms (Lorefalt et al., 2004) or to disease-related olfactory disorders (Chen et al., 2003; Cheshire and Wszolek, 2005), decreased nutrient absorption due to alterations in the autonomic nervous system as well as changes in the hypothalamic regulation of appetite (Broussolle et al., 1991; Chen et al., 2003; Pahlagen et al., 2005). However, no study to date has clearly validated these hypotheses, and one study even reported an increase in food intake (Broussolle et al., 1991). Furthermore, our data show for the first time that EE during any daily activity is substantially increased during motor fluctuations in Parkinson's disease. This observation corroborates the significant increase in BMR without L-dopa treatment described in the literature (Macia et al., 2004; Perlemoine et al., 2005) and reproduced in the study. Although little is known about the mechanisms of action (Gurrera, 1999), we may hypothesize that changes in EE are due to muscle tone and metabolic activity. This may be caused by dopamine deficiency-mediated alterations in autonomous muscle sympathetic nerve activity (Gurrera, 1999). We propose that the increased daily EE of Parkinsonian patients is mainly related to motor fluctuations.

EE during sleep and rest is often characterized by large fluctuations in Parkinson patients. Kinetics of EE were therefore analysed with caution. In particular, BMR was integrated over 45 min and SMR was determined during the night from the most stable periods of EE associated with low heart rate. The present study highlights that Parkinson's disease is associated with gender-specific alterations in energy metabolism which might involve alterations in the central control of energy metabolism. The mechanisms underlying the gender effect on energy metabolism are still unknown and deserve further investigations. Contrasting differences have been observed between disease-associated changes in BMR and SMR in male patients. In agreement with previous studies (Levi et al., 1990; Markus et al., 1992; Palhagen et al., 2005), we found that BMR, which is the EE of resting awakened fasting subjects, was higher in male patients on long-term L-dopa treatment than expected from predicted BMR. The increased in BMR may be explained by increased muscle rigidity—despite L-dopa treatment—and/or by LIDs (Lorefalt et al., 2004) due to alterations in the central regulation of energy metabolism (Gurrera, 1999). In contrast with BMR, we found that SMR, the EE of sleeping fasting subjects, was similar to that of healthy controls after adjustment for differences in lean body mass. SMR is the minimal EE of subjects. It is mainly determined by the metabolic activity of tissues and organs such as the liver and the heart. SMR differs from BMR as it is characterized by decreased muscle tone and brain activity, and decreased body core temperature. Therefore, the difference between SMR and BMR might be related to changes in muscle tone or to a higher fall in body core temperature during sleep.

DBS-STN induced a strong improvement (+60%) in the motor component of the UPDRS scales. Furthermore, motor complications such as motor fluctuations and LIDs as well as the antiparkinsonian medications were dramatically reduced after surgery. As expected from the literature (Gironell et al., 2002; Barichella et al., 2003; Macia et al., 2004; Tuite et al., 2005; Perlemoine et al., 2005), substantial body weight gain was observed 3 months after surgery. However, the body weight gain showed high inter-individual variability (ranging from –1.5 to 7.9 kg in males, and from 0.3 to 5.2 kg in females) and its quality was gender-specific. Two-thirds of the body weight gain in men was attributable to an increase in FFM as a consequence of gains in muscle mass and trunk FFM, which translated as an enlarged liver and gut, because the subjects were gaining weight. Muscle mass accretion could be explained by an increased IGF-1 production due to a better nutritional state (Raynaud-Simon et al., 2002) or, more probably, by increased physical activity levels, but not by changes in testosterone production. In contrast, women only gained fat, thus demonstrating that the anabolic response associated with an improved nutritional state is gender-specific. This observation questioned therefore whether body weight gain should be considered as deleterious for both gender or whether it might even be considered as beneficial for male patients suffering from weight loss.

Interestingly, the SMR of Parkinsonian men increased after STN-DBS. Furthermore, the BMR of Parkinsonian males with stimulation 'on' was not significantly different from predicted values, which contrasted with the pre-operative observations. Changes in SMR was mainly explained by FFM accretion, but the patterns of change in SMR and BMR both demonstrated that STN-DBS restored the energy metabolism of male Parkinsonian patients to the same levels as healthy controls. In contrast, daily EE in the calorimetric chambers (as well as the energy expended during daily activities) decreased significantly, i.e. by 7–13%, in both men and women. This suggests that, generally speaking, the DBS-STN-induced normalization of energy metabolism had similar consequences in both genders. The reduction of EE may be due to the reduction of muscle tone related to a decrease in motor fluctuations or to a resolution of LIDs. However, changes in the central regulation of energy metabolism might also be involved. Indeed, it cannot be excluded that there may be regional effects of DBS-STN on hypothalamic centres depending on the exact location of the contacts in the STN area, which would explain the variability of the weight gain. In fact, several hypothalamic fibres cross close to the STN (Lipp et al., 2005). Furthermore, studies in rats have provided suggestive evidence that dorsomedial hypothalamic sites are involved in thermogenesis (DiMicco et al., 2002). Therefore, the underlying mechanisms may involve an effect of STN-DBS on the activity of the sympathetic nervous system which partly influences tissue or organ metabolic activity (Gurrera, 1999).

In agreement with previous studies (Ondo et al., 2000; Baricella et al., 2003; Macia et al., 2004; Tuite et al., 2005; Perlemoine et al., 2005), daily energy intake was not altered after surgery. Inaccuracy inherent to self-reported food intake measurement should prompt caution in the interpretation of the results. However, our team and others (Baricella et al., 2003; Tuite et al., 2005; Perlemoine et al., 2005) have highlighted that normalization of energy metabolism is an important factor contributing to body weight gain after DBS-STN. Based on our results, we can further propose that the decrease in daily EE may promote body weight gain. Indeed, it is evident that the physical activity programme in the calorimetric chambers was standardized and did not reproduce free living conditions. However, patients followed the same activity programme before and after surgery. In particular, duration and recommendation for exercise intensity were similar before and after surgery. In this context, we were able to determine with precision the DBS-STN-induced changes on EE of daily activities. This allowed us to speculate on the consequences on free living daily EE: if EE of all light and moderate daily activities is reduced after surgery, this suggests that this component of free living daily EE is likely decreased. Our limit is that we did not take into account other factors, such as hormones (e.g. adipocytokines) involved in energy metabolism (Auwerx, 2006) or changes in spontaneous physical activity which probably play a crucial role in determining the risk of body weight gain. In that respect, we did not observe significant association between body weight gain and changes in UPDRS IV score and sub-scores which contrasts with results from Barichella et al. (2003). However, we found that high post-surgery improvements in patients with high pre-operative UPDRS III scores were correlated with lower body weight gains. Therefore, we may hypothesize that subjects who greatly improved their motor fluctuations may have increased their spontaneous physical activities because their quality of life was improved. The extra cost of these activities may compensate for the decreased EE due to the normalization of the energy metabolism and may prevent body weight gain.

In conclusion, DBS-STN implantation leads to body weight gain in both male and female patients with Parkinson's disease. The risk of body weight gain is highly variable among patients and differs between genders. As men gained primarily FFM, a reasonable weight gain may be tolerated, in contrast with women who gained only fat. Parkinson's disease is associated with profound alterations in energy metabolism that are normalized after DBS-STN implantation. These modifications are more pronounced in men but are not related to changes in testosterone production. Restoration of energy metabolism and decreased EE due to improved motor control and/or disappearance of LIDs are propitious for body weight gain. Therefore, the pragmatic and clinical application of these results is that patients should be advised on how to reduce energy intake, especially lipid intakes which are known to favour rapid body weight gain. Furthermore, the patients should be placed on progressive physical training programs in the early days following brain surgery in order to compensate for the major decrease daily EE caused by DBS-STN.


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