Association between the indole pathway of tryptophan metabolism and subclinical depressive symptoms in obesity: a preliminary study.

Converging data support the role of chronic low-grade inflammation in depressive symptomatology in obesity. One mechanism likely to be involved relies on the effects of inflammation on tryptophan (TRP) metabolism. While recent data document alterations in the indole pathway of TRP metabolism in obesity, the relevance of this mechanism to obesity-related depressive symptoms has not been investigated. The aim of this preliminary study was to assess the association between plasma levels of TRP and indole metabolites and depressive symptoms in 44 subjects with severe or morbid obesity, free of clinically relevant neuropsychiatric disorders. The interaction effect of inflammation, reflected in serum high-sensitive C-reactive protein (hsCRP) levels, and indoles on depressive symptoms was also determined. Higher serum levels of hsCRP and lower concentrations of TRP and indoles, particularly indole-3-carboxaldehyde (IAld), correlated with more severe depressive symptoms. Interestingly, the effect of high hsCRP levels in predicting greater depressive symptoms was potentiated by low IAld levels. These results comfort the link between inflammation, the indole pathway of TRP metabolism, and obesity-related depressive symptoms.

Transcriptomic signaling pathways involved in a naturalistic model of inflammation-related depression and its remission.

This study aimed at identifying molecular biomarkers of inflammation-related depression in order to improve diagnosis and treatment. For this, we performed whole-genome expression profiling from peripheral blood in a naturalistic model of inflammation-associated major depressive disorder (MDD) represented by comorbid depression in obese patients. We took advantage of the marked reduction of depressive symptoms and inflammation following bariatric surgery to test the robustness of the identified biomarkers. Depression was assessed during a clinical interview using Mini-International Neuropsychiatric Interview and the 10-item, clinician-administered, Montgomery-Asberg Depression Rating Scale. From a cohort of 100 massively obese patients, we selected 33 of them for transcriptomic analysis. Twenty-four of them were again analyzed 4-12 months after bariatric surgery. We conducted differential gene expression analyses before and after surgery in unmedicated MDD and non-depressed obese subjects. We found that TP53 (Tumor Protein 53), GR (Glucocorticoid Receptor), and NFκB (Nuclear Factor kappa B) pathways were the most discriminating pathways associated with inflammation-related MDD. These signaling pathways were processed in composite z-scores of gene expression that were used as biomarkers in regression analyses. Results showed that these transcriptomic biomarkers highly predicted depressive symptom intensity at baseline and their remission after bariatric surgery. While inflammation was present in all patients, GR signaling over-activation was found only in depressed ones where it may further increase inflammatory and apoptosis pathways. In conclusion, using an original model of inflammation-related depression and its remission without antidepressants, we provide molecular predictors of inflammation-related MDD and new insights in the molecular pathways involved.

Relationship between body mass index and neuropsychiatric symptoms: Evidence and inflammatory correlates.

OBJECTIVE: Neuropsychiatric symptoms are frequent in obese individuals. Mounting evidence suggests that adiposity-related inflammation contributes to this effect. This study assessed the relationship between adiposity, neuropsychiatric symptom dimensions and systemic inflammation in subjects stratified by body-mass-index (BMI). METHODS: The study included 165 subjects, of whom 70 were very severely obese (BMI ≥ 40 kg/m2), 50 severely obese (BMI: 35-39.99 kg/m2), 21 overweight or moderately obese (BMI: 25-34.9 kg/m2), and 24 lean (BMI < 25 kg/m2). Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Mini-International Neuropsychiatric Interview (MINI). Fatigue and general neurobehavioral symptoms were assessed using the Multidimensional Fatigue Inventory (MFI) and Neurotoxicity Rating Scale (NRS) respectively. Serum levels of the inflammatory markers, high-sensitive (hs) CRP and hsIL-6, were determined by ELISA. RESULTS: Severely obese subjects exhibited higher MADRS, MFI and NRS scores and were more frequently afflicted with current diagnosis of major depression than lean participants. Scores on psychometric scales were also increased in very severely obese subjects, although to a lesser extent. Alterations in neuropsychiatric dimensions were highly inter-related. HsCRP was significantly increased in subjects with severe or very severe obesity, while hsIL-6 was augmented in all obese groups. Overall, increased neuropsychiatric comorbidity was associated with greater systemic inflammation, notably hsCRP. CONCLUSION: Obesity is characterized by an increased prevalence of inter-related neuropsychiatric symptoms together with low-grade systemic inflammation augmenting with adiposity. The association between adiposity, systemic inflammation and neuropsychiatric alterations supports the contribution of adiposity-related inflammatory processes to neuropsychiatric comorbidities in obesity. These data suggest that consideration of adiposity characteristics may help identifying subjects at increased risk for neuropsychiatric comorbidity.

Tryptophan Metabolic Pathways Are Altered in Obesity and Are Associated With Systemic Inflammation.

Background: Obesity is a condition with a complex pathophysiology characterized by both chronic low-grade inflammation and changes in the gut microbial ecosystem. These alterations can affect the metabolism of tryptophan (TRP), an essential amino acid and precursor of serotonin (5-HT), kynurenine (KYN), and indoles. This study aimed to investigate alterations in KYN and microbiota-mediated indole routes of TRP metabolism in obese subjects relatively to non-obese controls and to determine their relationship with systemic inflammation. Methods: Eighty-five obese adults (avg. BMI = 40.48) and 42 non-obese control individuals (avg. BMI = 24.03) were recruited. Plasma levels of TRP catabolites were assessed using Ultra High Performance Liquid Chromatography-ElectroSpray-Ionization-Tandem Mass Spectrometry. High-sensitive C-reactive protein (hsCRP) and high-sensitive interleukin 6 (hsIL-6) were measured in the serum as markers of systemic inflammation using enzyme-linked immunosorbent assay. Results: Both KYN and microbiota-mediated indole routes of TRP metabolism were altered in obese subjects, as reflected in higher KYN/TRP ratio and lower 5-HT and indoles levels, relatively to non-obese controls. HsIL-6 and hsCRP were increased in obesity and were overall associated with TRP metabolic pathways alterations. Conclusion: These results indicate for the first time that KYN and indole TRP metabolic pathways are concomitantly altered in obese subjects and highlight their respective associations with obesity-related systemic inflammation.

Reward-related brain activity and behavior are associated with peripheral ghrelin levels in obesity.

BACKGROUND/OBJECTIVES: While excessive food consumption represents a key factor in the development of obesity, the underlying mechanisms are still unclear. Ghrelin, a gut-brain hormone involved in the regulation of appetite, is impaired in obesity. In addition to its role in eating behavior, this hormone was shown to affect brain regions controlling reward, including the striatum and prefrontal cortex, and there is strong evidence of impaired reward processing in obesity. The present study investigated the possibility that disrupted reward-related brain activity in obesity relates to ghrelin deficiency. SUBJECTS/METHODS: Fifteen severely obese subjects (BMI > 35 kg/m2) and fifteen healthy non-obese control subjects (BMI < 30 kg/m2) were recruited. A guessing-task paradigm, previously shown to activate the ventral striatum, was used to assess reward-related brain neural activity by functional magnetic resonance imaging (fMRI). Fasting blood samples were collected for the measurement of circulating ghrelin. RESULTS: Significant activations in the ventral striatum, ventromedial prefrontal cortex and extrastriate visual cortex were elicited by the fMRI task in both obese and control subjects. In addition, greater reward-related activations were present in the dorsolateral prefrontal cortex, and precuneus/posterior cingulate of obese subjects compared to controls. Obese subjects exhibited longer choice times after repeated reward and lower circulating ghrelin levels than lean controls. Reduced ghrelin levels significantly predicted slower post-reward choices and reward-related hyperactivity in dorsolateral prefrontal cortices in obese subjects. CONCLUSION: This study provides evidence of association between circulating ghrelin and reward-related brain activity in obesity and encourages further exploration of the role of ghrelin system in altered eating behavior in obesity.

History of major depression is associated with neuropsychiatric symptoms but not systemic inflammation in a cross-sectional study in obese patients.

Obesity is a major public health burden associated with neuropsychiatric comorbidities leading to social and occupational impairment. Given the growing prevalence of both obesity and mental disorders worldwide, understanding the risk factors of obesity-related neuropsychiatric comorbidities is crucial to develop preventive strategies and individualized treatments. Recent findings suggest that adiposity-driven inflammation contributes to neuropsychiatric comorbidities in obesity. However, not all obese subjects afflicted with chronic inflammation develop neuropsychiatric symptoms, suggesting additional risk factors. The aim of this study was to investigate the impact of personal history of major depressive disorder (MDD) on obesity-related inflammation and neuropsychiatric symptoms, and their relationship. A case-control study was conducted comparing 66 obese patients (body mass index > 35 kg/m2) and 22 healthy non-obese participants, free of any current neuropsychiatric diseases including MDD. Neuropsychiatric symptoms were assessed using the Neurotoxicity Rating Scale (NRS). Sociodemographic and clinical variables were gathered and blood was collected for the measurement of serum levels of high-sensitivity C-reactive protein (hs-CRP). Multiple regression analyses were performed to assess the contribution of obesity and personal history of MDD to clinical outcomes and inflammatory status in study participants. Hs-CRP levels as well as NRS scores were significantly increased in the obese group. Overall, personal history of depression accounted for increased NRS scores but no significant association was found with inflammatory status. In addition, history of depression did not significantly modulate the relationship of obesity-related inflammation with NRS scores. Interestingly, obese individuals with history of recurrent MDD (n = 13) exhibited higher scores in the cognitive and sickness symptoms dimensions of the NRS compared to obese subjects with history of one depressive episode only. Findings indicate that history of depression contributes to neuropsychiatric symptoms, but not to systemic inflammation, in obese subjects free of current depressive episode. These results provide relevant information on the risk factors that may help identify obese subjects with increased risk of neuropsychiatric comorbidity.

Depressive symptoms in obesity: Relative contribution of low-grade inflammation and metabolic health.

BACKGROUND: Recent reports suggest that the risk of depressive symptoms in obesity is potentiated in subjects presenting a metabolically unhealthy phenotype. Inflammation is often considered a defining criteria of metabolic health. However, this factor may drive the association of metabolic health with depressive symptoms given its well-known role in the pathophysiology of depression. This study aimed at determining the relative contribution of inflammation and metabolic abnormalities to depressive symptoms in obesity. METHODS: One-hundred severely obese adults (BMI ≥ 35-40 kg/m2) and 25 non-obese control individuals (BMI < 30 kg/m2) were recruited. Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and Mini-International Neuropsychiatric Interview (MINI). Serum high-sensitive C-reactive protein (hs-CRP) was measured as a marker of systemic inflammation. Metabolically unhealthy obesity was defined as obesity associated with two or more metabolic alterations, including low high-density lipoprotein cholesterol, hypertriglyceridemia, high fasting glucose and hypertension. RESULTS: Total MADRS scores were significantly higher in obese subjects with significant inflammation (hs-CRP ≥ 5 mg/L) compared to those with low inflammation (hs-CRP < 5 mg/L) and non-obese controls. Interestingly, hs-CRP levels significantly predicted MADRS scores in the whole population under study and in the group of obese subjects. Overall, no association was found between MADRS scores and individual metabolic alterations or the composite measure of metabolically unhealthy obesity. Similarly, the association of hs-CRP with MADRS scores in obese patients was not modulated by metabolic health factors. CONCLUSIONS: These results indicate that systemic inflammation represents a stronger contributor of obesity-related depressive symptoms than metabolic health per se. This supports the notion that inclusion of inflammation in the definition of metabolically unhealthy obesity drives the association found between poor metabolic health and depressive symptoms.

Low-grade inflammation is a major contributor of impaired attentional set shifting in obese subjects.

Impairment in cognitive flexibility and set shifting abilities has been described in obesity. This alteration is critical as it can interfere with obesity management strategies. Recent evidences suggest that chronic low-grade inflammation may be involved in cognitive deficits associated with obesity, but the potential involvement in reduced flexibility remains unknown. The objective of this study was to assess the contribution of low-grade inflammation, determined by circulating levels of high-sensitivity C-reactive protein (hsCRP), in reduced cognitive flexibility and shifting abilities of obese subjects relatively to a group of non-obese participants. Performance in the intra/extra-dimensional set shift (IED) test, extracted from the CANTAB, was assessed in 66 obese subjects and 20 non-obese participants. Obese subjects with concentrations of hsCRP above 5mg/L exhibited reduced performance on the IED test in comparison to obese subjects with lower levels of hsCRP and non-obese participants. This difference was particularly manifest in the number of errors made during the extra-dimensional shift (EDS errors). In contrast, performance before the extra-dimensional shift was spared. Linear regression analyses revealed that the association between obesity and IED alterations was significant only when the condition hsCRP >5mg/L was entered in the model. These findings are important as they indicate that, rather than obesity itself, low-grade inflammation represents a major contributor of IED performance in obese subjects.

Adipose inflammation in obesity: relationship with circulating levels of inflammatory markers and association with surgery-induced weight loss.

CONTEXT: The inflammatory state of the adipose tissue is believed to contribute to systemic low-grade inflammation in obesity. OBJECTIVE: This study assessed the relationship between adipose and circulating inflammatory markers as well as the influence of adipose inflammation on bariatric surgery-induced weight reduction. DESIGN: This was a cross-sectional and longitudinal study (up to 14 mo). SETTING: The study was conducted in the digestive/bariatric surgery department of the Tivoli and Jean Villar clinics, Bordeaux, France. PATIENTS: Thirty-seven obese patients [body mass index (BMI)>35-40 kg/m2)] seeking bariatric surgery were included. Twenty-eight of them were successively followed up at 1-3 months after surgery and 25 between 6 and 14 months after surgery. MAIN OUTCOME MEASURES: Fasting serum samples were collected before surgery to assess concentrations of inflammatory markers. Samples of visceral adipose tissue were extracted during surgery and gene expression of cytokines and immune cell markers were evaluated using quantitative RT-PCR. Pre- and postsurgery weight and BMI were collected. RESULTS: Gene expression of several cytokines were strongly intercorrelated in the visceral adipose tissue. Adipose expression of macrophage and T cell markers were related to adipose expression of TNF-α and IL-1 receptor antagonist (P<.01) and to systemic levels of TNF-α (P<.01) and IL-6 (P<.05). A higher inflammatory state of the adipose tissue predicted a lower BMI reduction after surgery (P<.05), notably at early stages after surgery. CONCLUSIONS: These findings support the involvement of macrophages and T cells in adipose inflammation and provide new information regarding the role of the visceral adipose tissue in the inflammatory state of obesity and its impact on obesity treatment outcomes, such as surgery-induced weight loss.

A single-institution prospective study of laparoscopic pancreatic resection.

HYPOTHESIS: Laparoscopic pancreatic resection can safely duplicate all of the open pancreatic procedures. DESIGN: A prospective evaluation of laparoscopic pancreatic resection. Surgical procedure, postoperative course, and follow-up data were collected. SETTING: Department of Abdominal Surgery at Haut-Lévêque Hospital, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France. PATIENTS: Sixty patients with presumed pancreatic neoplasms. Final diagnoses were benign disease in 57 patients (95%) and malignant pancreatic disease in 3 patients (5%). MAIN OUTCOME MEASURES: Complication and success rates of resections. RESULTS: Twenty percent of procedures were switched to open laparotomy. Laparoscopically successful procedures included 20 distal pancreatectomies with spleen preservation, 5 distal splenopancreatectomies, 16 enucleations, 5 medial pancreatectomies, 1 pancreatoduodenectomy, and 1 total pancreatectomy. Postoperative death occurred in 1 patient (1.6%). The overall postoperative complication rate was 36%, including a 13% rate of clinical fistulae. In successful laparoscopic operations, the mean (SD) postoperative hospital stay was 12.7 (6) days. Multivariate, stepwise analysis identified pancreatic consistency and pancreatic resection that required anastomosis as independent factors of postoperative complication (P = .02 and P = .002, respectively). The 3 patients operated on for pancreatic malignancies were still alive at follow-up (median, 23 months); all patients with benign disease were alive at long-term follow-up. CONCLUSIONS: This series demonstrates that laparoscopic pancreatic resection is not only feasible but also safe. Our study suggests that the best indications for a laparoscopic approach are presumably benign pancreatic tumors not requiring pancreaticoenteric reconstruction.

Laparoscopic central pancreatectomy: single institution experience of 6 patients.

BACKGROUND: Medial pancreatectomy is an alternative technique for benign or low-grade malignant tumors of the neck of the pancreas. We describe our experience of laparoscopic central pancreatectomy. METHODS: We conducted a prospective evaluation of laparoscopic pancreatic resection in the Department of Abdominal Surgery at Haut-Lévêque Hospital, CHU Bordeaux. From January 1999 until February 2006, 397 patients underwent pancreatic resection for pancreatic lesions, of whom 60 (15%) were enrolled for laparoscopic pancreatic resection. Of the 60 patients, 6 underwent laparoscopic central pancreatectomy. Surgical procedure, postoperative course, and follow-up data were collected. RESULTS: Laparoscopic central pancreatectomy was successful in all patients. In 1 case, we had to perform a laparotomy to find the specimen, which had been lost in the cavity during the anastomosis. The median operative time was 225 minutes (range, 180 to 365 minutes). None of the patients required blood transfusion in the perioperative period, and there was no mortality. Symptomatic pancreatic fistula occurred in 2 patients (33%). None of the patients required reoperation or radiologic drainage. Oral feeding was resumed in a median of 11 days (range, 9 to 21 days). The median postoperative hospital stay was 18 days (range, 15 to 25 days). At a median follow-up of 15 months (range, 4 to 34 months), all patients were alive without exocrine or endocrine insufficiency. CONCLUSIONS: Laparoscopic central pancreatectomy is feasible and safe. Laparoscopic central pancreatectomy may become the standard approach for resection of benign or low-grade malignant tumors of the neck of the pancreas if performed by highly skilled surgeons.

Laparoscopic versus open approach for solitary insulinoma.

BACKGROUND: In recent years, advances in laparoscopic techniques have allowed surgeons to treat pancreatic lesions laparoscopically. Insulinoma, the most prevalent pancreatic endocrine tumor, is mostly benign and curable with surgical resection. This study aimed to assess the results from laparoscopic resection (LG) of insulinomas and to compare them with the results from open surgery (OG). METHODS: From September 1999 to December 2005, 56 laparoscopic pancreatic resections were performed for selected patients, including 12 laparoscopic resections of insulinomas. The results were compared with those of patients who underwent open resection of insulinomas selected from the authors' pancreatic database. RESULTS: Three conversions to the open approach were required because of inability to identify the tumor. There were no deaths in either group, and the morbidity rates were 25% (3/12) for LG and 55% (5/9) for OG (nonsignificant difference). The pancreatic fistula rate after laparoscopic enucleation was statistically lower than after open enucleation (14% vs 100%; p = 0.015). The mean postoperative hospital stay was 13 +/- 5.9 days for LG and 17.6 +/- 7.5 days for OG (nonsignificant difference). After exclusion of the patients who underwent conversion to laparotomy, the mean postoperative hospital stay was 11.5 +/- 5.8 days for LG and 17.6 +/- 7.5 days for OG (p = 0.04). CONCLUSION: This study demonstrates the feasibility and safety of laparoscopic resection of insulinomas. The laparoscopic approach was associated with a decrease in hospital stay and pancreatic fistula after enucleation. Preoperative localization tests and laparoscopic ultrasonography seem necessary to prevent conversion.