Alcohol and Other Addictive Disorders Following Bariatric Surgery: Prevalence, Risk Factors and Possible Etiologies.

Bariatric surgery is currently the most effective intervention for significant and sustained weight loss in obese individuals. While patients often realize numerous improvements in obesity-related comorbidities and health-related quality of life, a small minority of patients have less optimal outcomes following bariatric surgery. The literature on the emergence of alcohol use disorders (AUDs) following bariatric surgery has grown in the past several years and collectively provides convincing evidence that a significant minority of patients develop new-onset AUDs following bariatric surgery. Rouxen-Y gastric bypass (RYGB) has generally been associated with the risk of developing an AUD, while laparoscopic adjustable gastric banding generally has not, in several large studies. One theory that has been discussed at some length is the idea of 'addiction transfer' wherein patients substitute one 'addiction' (food) for a new 'addiction' (alcohol) following surgery. Animal work suggests a neurobiological basis for increased alcohol reward following RYGB. In addition, several pharmacokinetic studies have shown rapid and dramatically increased peak alcohol concentrations following RYGB. The prevalence of alcohol and other addictive disorders and potential etiological contributors to post-operative AUDs will be explored.

Psychiatric aspects of bariatric surgery.

While most conventional treatments for individuals with severe obesity have a modest and short lived impact bariatric surgery has been consistently shown to result in long-term marked weight loss and significant improvement in medical comorbidities. Empirical data suggest a high prevalence of mental disorders among bariatric surgery candidates. This article reviews specific areas of psychopathology, problems in using psychopharmacological medications post-surgery, body contouring, and recommendations for pre and post-surgery care. Available research indicates a decrease in psychiatric symptoms post-surgery. However, in some patients the improvement appears to erode over time. Therefore, bariatric surgery patients should be monitored not only before surgery but also following surgery and referred for mental health treatment if problems develop.

Adhesion of monocytes to type I collagen stimulates an APP-dependent proinflammatory signaling response and release of Abeta1-40.

BACKGROUND: Amyloid precursor protein (APP) is a ubiquitously expressed cell surface protein reported to be involved in mediating cell-cell or cell-matrix interactions. Prior work has demonstrated that APP co-localizes with beta1 integrin in different cell types. METHODS: In an effort to determine the function of APP on monocytic lineage cells, in particular, the human monocyte cell line, THP-1, was used to assess the role of APP during adhesion to the extracelluar matrix component type I collagen. RESULTS: Pull-down assays demonstrated that THP-1 adhesion to collagen stimulated a tyrosine kinase-associated signaling response which included subsequent phosphorylation of p38 MAP kinase and increased association of APP with alpha2beta1 integrin, specifically. In addition, cell adhesion was dependent upon APP expression since APP siRNA knockdown attenuated THP-1 adhesion to collagen compared to mock transfected controls. One consequence of the tyrosine kinase-dependent signaling response was increased secretion of interleukin-1beta (IL-1beta) and Abeta1-40 but not the Abeta1-42 fragment of APP. Increased secretion of IL-1beta was dependent upon p38 MAP kinase activity while Abeta1-40 secretion required Src family kinase activity since the specific p38 inhibitor, SB202190, and the Src family kinase inhibitor, PP2, attenuated IL-1beta and Abeta1-40 secretion, respectively. CONCLUSIONS: These data demonstrate that APP is involved in classic integrin-dependent tyrosine kinase-associated adhesion and activation of peripheral monocytic cells. Moreover, divergent APP-dependent signaling is required for increased secretion of both IL-1beta and Abeta1-40 as a component of the adhesion-dependent change in phenotype. This suggests that APP may have a broad role in not only mediating cell-matrix adhesion but also in the function of peripheral immune cells.

Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia.

BACKGROUND: Beta amyloid (Abeta) peptides are the major constituents of the senile plaques present in Alzheimer's diseased brain. Pathogenesis has been associated with the aggregated form of the peptide as these fibrils are the conformation readily found in the plaques. However, recent studies have shown that the nonaggregated, soluble assemblies of Abeta have the potential to stimulate neuronal dysfunction and may play a prominent role in the pathogenesis of Alzheimer's disease. METHODS: Soluble, synthetic Abeta1-42 oligomers were prepared producing mainly dimer-trimer conformations as assessed by SDS-PAGE. Similar analysis demonstrated fibril preparations to produce large insoluble aggregates unable to migrate out of the stacking portion of the gels. These peptide preparations were used to stimulate primary murine microglia and cortical neuron cultures. Microglia were analyzed for changes in signaling response and secretory phenotype via Western analysis and ELISA. Viability was examined by quantifying lactate dehydrogenase release from the cultures. RESULTS: Abeta oligomers and fibrils were used to stimulate microglia for comparison. Both the oligomers and fibrils stimulated proinflammatory activation of primary microglia but the specific conformation of the peptide determined the activation profile. Oligomers stimulated increased levels of active, phosphorylated Lyn and Syk kinase as well as p38 MAP kinase compared to fibrils. Moreover, oligomers stimulated a differential secretory profile for interleukin 6, monocyte chemoattractant protein-1 and keratinocyte chemoattractant when compared to fibrils. Finally, soluble oligomers stimulated death of cultured cortical neurons that was exacerbated by the presence of microglia. CONCLUSION: These data suggest that fibrils and oligomers stimulate unique signaling responses in microglia leading to discrete secretory changes and effects on neuron survival. This suggests that inflammation changes during disease may be the consequence of unique peptide-stimulated events and each conformation may represent an individual anti-inflammatory therapeutic target.

Addictive disorders after Roux-en-Y gastric bypass.

BACKGROUND: Recent literature suggests that some patients may develop addictive disorders after bariatric surgery, in particular after Roux-en-Y gastric bypass (RYGB). These may include traditional addictions and so called "behavioral addictions," although prevalence data on the latter have not been published. The objective of this study was to establish the prevalence of addictive behaviors in adults after RYGB. METHODS: Participants from a large observational study of bariatric surgery who had undergone RYGB were recruited to complete additional measures. Of 241 consented participants, 201 provided data (i.e., Structured Clinical Interview for DSM-IV Axis I [SCID], additional Impulsive Control Disorder Modules, and various self-report measures, including the Alcohol Use Disorder Identification Test [AUDIT]) to assess status before surgery and in the first 3 postoperative years. RESULTS: Based on the SCID, 16 (8.0%) developed alcohol use disorder [AUD] within 3 years post-RYGB, 7 (43.8%) of whom had no history of AUD. When both the SCID and AUDIT were used to identify AUD, the corresponding numbers/percentages were 32 (18.4%) and 13 (40.6%). Data on other behavioral addictive disorders indicated 19 (9.5%) had a postsurgery disorder, 6 (31.6%) of whom had no history. CONCLUSION: These data add to a growing literature suggesting there is a substantial risk for the development of AUD after bariatric surgery. Understanding the risk for nondrug-related addictive disorders requires more data from larger studies before clear conclusions can be drawn.

Amyloid precursor protein mediates proinflammatory activation of monocytic lineage cells.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by extracellular deposition of beta-amyloid (Abeta) peptide containing neuritic plaques. Abeta peptides are proteolytically derived from the membrane-bound amyloid precursor protein (APP). Although the function of APP is not entirely clear, previous studies demonstrate that neuronal APP colocalizes with beta(1) integrin receptors at sites of focal adhesion, suggesting that APP is involved in mediating neuronal process adhesion. Integrin-dependent adhesion is also a well-characterized component of immune cell proinflammatory activation. Using primary mouse microglia and the human monocytic cell line, THP-1, we have begun investigating the role of APP in integrin-dependent activation. Co-immunoprecipitation studies demonstrate that APP is recruited into a multi-receptor signaling complex during beta(1) integrin-mediated adhesion of monocytes. Stimulation induces a subsequent, specific recruitment of tyrosine phosphorylated proteins to APP, including Lyn and Syk. Antibody cross-linking of cell surface APP leads to a similar response characterized by activation and recruitment of tyrosine kinases to APP as well as subsequent activation of mitogen-activated protein kinases and increased proinflammatory protein levels. These data demonstrate that APP can act as a proinflammatory receptor in monocytic lineage cells and provide insight into the contribution of this protein to the inflammatory conditions described in Alzheimer's disease.