Post-sepsis syndrome - an evolving entity that afflicts survivors of sepsis.

BACKGROUND: The sequelae of sepsis were once thought to be independent of sepsis itself and assumed to be either comorbid to sick patients or complications of critical illness. Recent studies have reported consistent patterns of functional disabilities in sepsis survivors that can last from months to years after symptoms of active sepsis had resolved. BODY: Post-sepsis syndrome is an emerging pathological entity that has garnered significant interest amongst clinicians and researchers over the last two decades. It is marked by a significantly increased risk of death and a poor health-related quality of life associated with a constellation of long-term effects that persist following the patient's bout with sepsis. These include neurocognitive impairment, functional disability, psychological deficits, and worsening medical conditions. CONCLUSION: This "post-sepsis syndrome" has been the subject of active preclinical and clinical research providing new mechanistic insights and approaches linked to survivor well-being. Here we review important aspects of these research efforts and goals of care for patients who survive sepsis.

Reuniting overnutrition and undernutrition, macronutrients, and micronutrients.

Over-nutrition and its late consequences are a dominant theme in medicine today. In addition to the health hazards brought on by over-nutrition, the medical community has recently accumulated a roster of health benefits with obesity, grouped under "obesity paradox." Throughout the world and throughout history until the 20th century, under-nutrition was a dominant evolutionary force. Under-nutrition brings with it a mix of benefits and detriments that are opposite to and continuous with those of over-nutrition. This continuum yields J-shaped or U-shaped curves relating body mass index to mortality. The overweight have an elevated risk of dying in middle age of degenerative diseases while the underweight are at increased risk of premature death from infectious conditions. Micronutrient deficiencies, major concerns of nutritional science in the 20th century, are being neglected. This "hidden hunger" is now surprisingly prevalent in all weight groups, even among the overweight. Because micronutrient replacement is safe, inexpensive, and predictably effective, it is now an exceptionally attractive target for therapy across the spectrum of weight and age. Nutrition-related conditions worthy of special attention from caregivers include excess vitamin A, excess vitamin D, and deficiency of magnesium.

Newly diagnosed type 2 diabetes may serve as a potential marker for pancreatic cancer.

Pancreatic cancer has an extremely highly case fatality. Diabetes is a well-established strong risk factor for pancreatic cancer. Compared with a nondiabetic population, we previously reported a 15- and 14-fold greater risk for detecting pancreatic cancer during the first year after diagnosing diabetes in adult women and men, respectively, which dropped during the second year to 5.4-fold and 3.5-fold, respectively, and stabilized around 3-fold for the rest of the 11-year follow-up in our historical cohort. The population attributable risk during the 11-year period was 13.3% and 14.1% in prevalent diabetic women and men, respectively. This means that one out of about every 8 patients diagnosed with pancreatic cancer has been previously diagnosed with diabetes. The globally high prevalence of diabetes and the aggravating implications of a delayed pancreatic cancer diagnosis call for newly-onset diabetes to be considered a potential marker for an underlying pancreatic cancer and addressed accordingly.

Lessons learned from the 1-hour post-load glucose level during OGTT: Current screening recommendations for dysglycaemia should be revised.

This perspective covers a novel area of research describing the inadequacies of current approaches for diagnosing dysglycaemia and proposes that the 1-hour post-load glucose level during the 75-g oral glucose tolerance test may serve as a novel biomarker to detect dysglycaemia earlier than currently recommended screening criteria for glucose disorders. Considerable evidence suggests that a 1-hour post-load plasma glucose value ≥155 mg/dl (8.6 mmol/L) may identify individuals with reduced ß-cell function prior to progressing to prediabetes and diabetes and is highly predictive of those likely to progress to diabetes more than the HbA1c or 2-hour post-load glucose values. An elevated 1-hour post-load glucose level was a better predictor of type 2 diabetes than isolated 2-hour post-load levels in Indian, Japanese, and Israeli and Nordic populations. Furthermore, epidemiological studies have shown that a 1-hour PG ≥155 mg/dl (8.6 mmol/L) predicted progression to diabetes as well as increased risk for microvascular disease and mortality when the 2-hour level was <140 mg/dl (7.8 mmol/L). The risk of myocardial infarction or fatal ischemic heart disease was also greater among subjects with elevated 1-hour glucose levels as were risks of retinopathy and peripheral vascular complications in a Swedish cohort. The authors believe that the considerable evidence base supports redefining current screening and diagnostic recommendations with the 1-hour post-load level. Measurement of the 1-hour PG level would increase the likelihood of identifying a larger, high-risk group with the additional practical advantage of potentially replacing the conventional 2-hour oral glucose tolerance test making it more acceptable in a clinical setting.

Is metformin poised for a second career as an antimicrobial?

Metformin, a widely used antihyperglycaemic, has a good safety profile, reasonably manageable side-effects, is inexpensive, and causes a desirable amount of weight loss. In 4 studies of patients with tuberculosis (1 prospective and 3 retrospective), metformin administration resulted in better outcomes. In mice with several models of endotoxemia, metformin diminished levels of proinflammatory cytokines and improved survival. Laboratory studies showed effectiveness of the drug on multiple pathogens, including Trichinella spiralis, Staphylococcus aureus, Pseudomonas aeruginosa, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Metformin administration in humans and mice produced major changes in the composition of the gut microbiota. These recently discovered microbe-modulating properties of the drug have led investigators to predict wide therapeutic utility for metformin. The recent easing in United States Food and Drug Administration (FDA) guidelines regarding administration of metformin to patients with kidney disease, and reduced anxiety about patient safety in terms of lactic acidosis, increase the probability of broadening of metformin's usage as a treatment of infectious agents. In this text we review articles pertinent to metformin's effects on microorganisms, both pathogens and commensals. We highlight the possible role of metformin in a wide range of infectious diseases and a possible expansion of its therapeutic profile in this field. A systematic review was done of PubMed indexed articles that examined the effects of metformin on a wide range of pathogens. Metformin was found to have efficacy as an antimicrobial agent in patients with tuberculosis. Mice infected with Trypanosomiasis cruzi had higher survival when also treated with metformin. The drug in vitro was active against T. spiralis, S. aureus, P. aeruginosa, and hepatitis B virus. In addition there is emerging literature on its role in sepsis. We conclude that metformin may have a potential role in the therapy for multiple infectious diseases. Metformin, in addition to its traditional effects on glucose metabolism, provides anti-microbial benefits in patients with tuberculosis and in a very wide range of other infections encounters in vitro and in vivo.

Novel role of PKR in inflammasome activation and HMGB1 release.

The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1ß, IL-18 and high-mobility group box 1 (HMGB1). By studying HMGB1 release mechanisms, here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminium, rotenone, live Escherichia coli, anthrax lethal toxin, DNA transfection and Salmonella typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1ß, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell-free system with recombinant NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC, also known as PYCARD) and pro-caspase-1 reconstitutes inflammasome activity. These results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.

Obesity paradox, obesity orthodox, and the metabolic syndrome: An approach to unity.

Obesity and the accompanying metabolic syndrome are strongly associated with heightened morbidity and mortality in older adults. In our review of more than 20 epidemiologic studies of major infectious diseases, including leaders such as tuberculosis, community-acquired pneumonia, and sepsis, obesity was associated with better outcomes. A cause-and-effect relationship between over-nutrition and survival with infection is suggested by results of two preliminary studies of infections in mice, where high fat feeding for 8-10 weeks provided much better outcomes. The better outcomes of infections with obesity are reminiscent of many recent studies of "sterile" non-infectious medical and surgical conditions where outcomes for obese patients are better than for their thinner counterparts --- and given the tag "obesity paradox". Turning to the history of medicine and biological evolution, we hypothesize that the metabolic syndrome has very ancient origins and is part of a lifelong metabolic program. While part of that program (the metabolic syndrome) promotes morbidity and mortality with aging, it helps infants and children as well as adults in their fight against infections and recovery from injuries, key roles in the hundreds of centuries before the public health advances of the 20th century. We conclude with speculation on how understanding the biological elements that protect obese patients with infections or injuries might be applied advantageously to thin patients with the same medical challenges.

Alterations in pancreatic ß cell function and Trypanosoma cruzi infection: evidence from human and animal studies.

The parasite Trypanosoma cruzi causes a persistent infection, Chagas disease, affecting millions of persons in endemic areas of Latin America. As a result of immigration, this disease has now been diagnosed in non-endemic areas worldwide. Although, the heart and gastrointestinal tract are the most studied, the insulin-secreting ß cell of the endocrine pancreas is also a target of infection. In this review, we summarize available clinical and laboratory evidence to determine whether T. cruzi-infection-mediated changes of ß cell function is likely to contribute to the development of hyperglycemia and diabetes. Our literature survey indicates that T. cruzi infection of humans and of experimental animals relates to altered secretory behavior of ß cells. The mechanistic basis of these observations appears to be a change in stimulus-secretion pathway function rather than the loss of insulin-producing ß cells. Whether this attenuated insulin release ultimately contributes to the pathogenesis of diabetes in human Chagas disease, however, remains to be determined. Since the etiologies of diabetes are multifactorial including genetic and lifestyle factors, the use of cell- and animal-based investigations, allowing direct manipulation of these factors, are important tools in testing if reduced insulin secretion has a causal influence on diabetes in the setting of Chagas disease. Long-term clinical investigations will be required to investigate this link in humans.

Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice.

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by beta cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice. PEDF levels are significantly elevated in pancreas, in correlation with pancreatic TNF levels in NOD mice. To identify experimental therapeutics, we screened 2,327 compounds in two chemical libraries (the NIH Clinical Collection and Pharmakon-1600a) for leads that inhibit PEDF mediated TNF release in macrophage cultures. The lead molecule selected, "emetine" is a widely used emetic. It inhibited PEDF-mediated macrophage activation with an EC50 or 146 nM. Administration of emetine to NOD mice and to C57Bl6 mice subjected to streptozotocin significantly attenuated hyperglycemia, reduced TNF levels in pancreas, and attenuated insulitis. Together, these results suggest that targeting PEDF with emetine may attenuate TNF release and hyperglycemia in murine diabetes models. This suggests that further investigation of PEDF and emetine in the pathogenesis of human diabetes is warranted.

Dysglycemia and long-term mortality: observations from the Israel study of glucose intolerance, obesity and hypertension.

BACKGROUND: We describe the relationship between dysglycemia and long-term mortality and elucidate the relationship between blood glucose levels during an oral glucose tolerance test (OGTT) and haemoglobin A1 (HbA1) and mortality. METHODS: A cohort of 1410 individuals was followed for 33 years since 1980. Fasting and post-OGTT glucose parameters were used to categorize the cohort according to baseline glycemic status. RESULTS: The mortality rate increased from 43% in normoglycemic individuals to 53.3, 61.7, 72.9 and 88.0% in those with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG/IGT and diabetes, respectively. The highest mortality rate, compared with the normoglycemic category, was observed in individuals with IFG/IGT and diabetes according to a Cox proportional hazard model (HR = 1.38, 95%CI 1.10-1.74 and HR = 2.14, 95%CI 1.70-2.70, respectively), followed by individuals with IGT and IFG, but this did not reach statistical significance. We speculate that the IFG group may represent a mixture of individuals en route from normal to the next two categories as well as another cohort whose glucose levels are stably set at the upper reaches of the normal distribution. Significant differences were found between 1 and 2 h glucose values (p < 0.001). Fasting, 60 and 120 min glucose values were positively associated with increasing HbA1 quintiles (p < 0.05). The mean HbA1 was significantly higher in those who died (p = 0.01). The highest mortality (58.8%) was observed in the upper HbA1 quintile that was also associated with the highest prevalence of the metabolic syndrome (17.2%). CONCLUSIONS: This study shows a continuous relationship between the severity of dysglycemia and long-term mortality and should promote the early recognition of prediabetes. The 1 h post-load glucose level was continuously associated with increasing HbA1 concentrations and may therefore serve as an early marker for abnormalities in glucose tolerance. An elevated 1 h post-load glucose level may potentially identify at-risk individuals well before the traditional 2 h glucose value.

Sex and ethnic-origin specific BMI cut points improve prediction of 40-year mortality: the Israel GOH study.

BACKGROUND: Although obesity has been associated with a higher risk for premature death, the sex and ethnic-origin specific body mass index (BMI) levels that are associated with increased mortality are controversial. We investigated the 40-year cumulative all-cause mortality, in relation to the BMI in adult life, among men and women originating from Yemen, Europe/America, Middle East and North Africa, using sex and ethnic-origin specific BMI cut points. METHODS: A random stratified cohort (n = 5710) was sampled from the central population registry and followed since 1969 for vital status. Weight, height and blood pressure were measured, and smoking status was recorded at baseline. BMI was analysed according to conventional categories and according to sex and ethnic-origin specific quintiles. RESULTS: Elevated and significant mortality hazard ratios (HRs) of 1.21 [95% confidence interval (CI) 1.00-1.45] for women and 1.22 (95%CI 1.03-1.44) for men were found for the highest origin-specific BMI quintile. In men, the lowest ethnic-origin specific quintile was also significantly associated with increased mortality (HR of 1.22 95% CI 1.03-1.45), adjusting for age, smoking and blood pressure. Obesity was associated with mortality in non-smokers (HR = 1.29, 95% CI 1.04-1.61 in men and HR = 1.46, 95% CI 1.19-1.79 in women), whereas leanness was associated with mortality only among smoking men (HR = 1.39, 95% CI 1.09-1.77). CONCLUSION: Refinement of BMI categories using country of origin specific quintiles demonstrated significantly increased mortality in the upper quintile in both sexes, while according to the conventional values this association did not prevail in men. We propose the establishment of sex and origin-specific BMI categories when setting goals for disease prevention.

The brighter (and evolutionarily older) face of the metabolic syndrome: evidence from Trypanosoma cruzi infection in CD-1 mice.

BACKGROUND: Infection with Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, results in chronic infection that leads to cardiomyopathy with increased mortality and morbidity in endemic regions. In a companion study, our group found that a high-fat diet (HFD) protected mice from T. cruzi-induced myocardial damage and significantly reduced post-infection mortality during acute T. cruzi infection. METHODS: In the present study metabolic syndrome was induced prior to T. cruzi infection by feeding a high fat diet. Also, mice were treated with anti-diabetic drug metformin. RESULTS: In the present study, the lethality of T. cruzi (Brazil strain) infection in CD-1 mice was reduced from 55% to 20% by an 8-week pre-feeding of an HFD to induce obesity and metabolic syndrome. The addition of metformin reduced mortality to 3%. CONCLUSIONS: It is an interesting observation that both the high fat diet and the metformin, which are known to differentially attenuate host metabolism, effectively modified mortality in T. cruzi-infected mice. In humans, the metabolic syndrome, as presently construed, produces immune activation and metabolic alterations that promote complications of obesity and diseases of later life, such as myocardial infarction, stroke, diabetes, Alzheimer's disease and cancer. Using an evolutionary approach, we hypothesized that for millions of years, the channeling of host resources into immune defences starting early in life ameliorated the effects of infectious diseases, especially chronic infections, such as tuberculosis and Chagas disease. In economically developed countries in recent times, with control of the common devastating infections, epidemic obesity and lengthening of lifespan, the dwindling benefits of the immune activation in the first half of life have been overshadowed by the explosion of the syndrome's negative effects in later life.

Urgent call for the third wish.

The people afflicted with obesity and its consequences need a menu of low-cost programmes to mitigate the over-nutrition and under-activity that underlie their condition. This editorial commentary points out the multiple merits (and shortcomings) of the Nordic walking - with ski poles - presented in an accompanying article. The Nordic exercise programme is then examined more broadly in the context of the general principles and limitations of exercise programmes - with and without calorie control - as a guide to future innovations.

The metabolic deterioration that antedates diabetes: personal trajectories of HbA(1c) and fasting glucose as early indicators and possible triggers for intervention.

HbA(1c) testing has become an accepted means of diagnosing diabetes as an alternative to blood glucose levels. However, population-based norms of glucose and of HbA(1c) levels do not enable the detection of diabetes at an early enough stage to thwart complications. Personal trajectories of glucose levels show steep increases a number of years prior to diabetes diagnosis. Here, we hypothesize that a comparable time-dependent deviation in an individual's HbA(1c) level may be an early manifestation of disease that should prompt lifestyle modifications. We predict that analysis of personal trajectories of glucose and of HbA(1c) will promote earlier intervention and a greater reduction in disease complications than current standards, which are based on population-based norms.

Increased plasma lipopolysaccharide-binding protein and altered inflammatory mediators in overweight women suggest a state of subclinical endotoxemia.

Chronic low-grade inflammation has been recognized as an underlying event linking obesity to cardiovascular disease (CVD). However, inflammatory alterations in individuals who are overweight remain understudied. To provide insight, we determined the levels of key circulating biomarkers of endotoxemia and inflammation, including lipopolysaccharide-binding protein (LBP), CRP, IL-6, leptin, and adiponectin in adult female subjects (n=40) who were lean or overweight and had high cholesterol and/or high blood pressure - two important conventional risk factors for CVD. Plasma levels of LBP were significantly higher in the overweight group compared with the lean group (P=0.005). The levels of CRP were also significantly higher in overweight subjects (P=0.01), as were IL-6 (P=0.02) and leptin (P=0.002), pro-inflammatory mediators associated with cardiovascular risk. Levels of adiponectin, an adipokine with anti-inflammatory and anti-atherogenic functions, were significantly lower in the overweight group (P=0.002). The leptin/adiponectin ratio, a preferential atherogenic marker was significantly increased in women who are overweight (P=0.02). LBP, CRP, leptin, and adiponectin levels significantly correlated with BMI, but not with age and there was a significant correlation between LBP and IL-6 levels. These results reveal the presence of subclinical endotoxemia and a pro-inflammatory state in overweight women and are of interest for further studies with the goal for improved understanding of cardiovascular health risks in women.

Glucagon-like peptide-1: a multi-faceted anti-inflammatory agent.

Inflammation contributes to many chronic conditions. It is often associated with circulating pro-inflammatory cytokines and immune cells. GLP-1 levels correlate with disease severity. They are often elevated and can serve as markers of inflammation. Previous studies have shown that oxytocin, hCG, ghrelin, alpha-MSH and ACTH have receptor-mediated anti-inflammatory properties that can rescue cells from damage and death. These peptides have been studied well in the past century. In contrast, GLP-1 and its anti-inflammatory properties have been recognized only recently. GLP-1 has been proven to be a useful adjuvant therapy in type-2 diabetes mellitus, metabolic syndrome, and hyperglycemia. It also lowers HbA1C and protects cells of the cardiovascular and nervous systems by reducing inflammation and apoptosis. In this review we have explored the link between GLP-1, inflammation, and sepsis.

Insulin's discovery: new insights on its ninetieth birthday.

2012 marks the 90th year since the purification of insulin and the miraculous rescue from death of youngsters with type 1 diabetes. In this review, we highlight several previously unappreciated or unknown events surrounding the discovery. (i) We remind readers of the essential contributions of each of the four discoverers--Banting, Macleod, Collip, and Best. (ii) Banting and Best (each with his own inner circle) worked not only to accrue credit for himself but also to minimize credit to the other discoverers. (iii) Banting at the time of the insulin research was very likely suffering from post-traumatic stress disorder (PTSD) that originated during his heroic service as a surgeon in World War I on the Western Front in 1918, including an infected shrapnel wound that threatened amputation of his arm. His war record along with the newly discovered evidence of a suicide threat goes along with his paranoia, combativeness, alcohol excess, and depression, symptoms we associate with PTSD. (iv) Banting's eureka idea, ligation of the pancreatic duct to preserve the islets, while it energized the early research, was unnecessary and was bypassed early. (v) Post discovery, Macleod uncovered many features of insulin action that he summarized in his 1925 Nobel Lecture. Macleod closed by raising the question--what is the mechanism of insulin action in the body?--a challenge that attracted many talented investigators but remained unanswered until the latter third of the 20th century.

Diabetes, glucose control, glucose lowering medications, and cancer risk: a 10-year population-based historical cohort.

BACKGROUND: Both diabetes and glucose-lowering medications have been associated with an increased risk of cancer incidence. This study will compare cancer incidence rates in individuals with and without diabetes; and will investigate, in individuals with diabetes, an association between glucose control and cancer incidence; and between the use of specific glucose-lowering medications, as well as no drug exposure, and cancer incidence. METHODS/DESIGN: This is a population based historical cohort study of all individuals aged 21 years or older (about 2,300,000) who were insured by Clalit Health Services, the largest health maintenance organization in Israel during a ten-year study period. Four study groups will be established according to the status of diabetes and cancer at study entry, Jan 1, 2002: cancer free, diabetes free; cancer free, diabetes prevalent; cancer prevalent, diabetes free; and cancer prevalent, diabetes prevalent. Individuals without diabetes at study entry will be followed for diabetes incidence, and all four groups will be followed for specific cancer incidence, including second primary neoplasms. Glucose control will be assessed by HbA1c and by fasting plasma glucose levels. Time dependent regression models for cancer incidence will account for glucose-lowering medications as they are added and changed over the follow-up period. A large number of demographic and clinical variables will be considered, including: age, gender, BMI, smoking status, concomitant medications, glucose control (assessed by HbA1c and by fasting plasma glucose) and cancer screening tests. DISCUSSION: Strengths of this study include the large population; high quality comprehensive data; comparison to individuals without diabetes, and to those with diabetes but not treated with glucose-lowering medications; and the extensive range of variables available for analysis. The great increases in diabetes prevalence and in treatment options render this study particularly relevant and timely. The Israeli national healthcare system, characterized by high standard and uniform healthcare, offers an advantageous environment for its conduct.

Oxytocin and Related Peptide Hormones: Candidate Anti-Inflammatory Therapy in Early Stages of Sepsis.

Sepsis is a potentially life-threatening systemic inflammatory syndrome characterized by dysregulated host immunological responses to infection. Uncontrolled immune cell activation and exponential elevation in circulating cytokines can lead to sepsis, septic shock, multiple organ dysfunction syndrome, and death. Sepsis is associated with high re-hospitalization and recovery may be incomplete, with long term sequelae including post-sepsis syndrome. Consequently, sepsis continues to be a leading cause of morbidity and mortality across the world. In our recent review of human chorionic gonadotropin (hCG), we noted that its major properties including promotion of fertility, parturition, and lactation were described over a century ago. By contrast, the anti-inflammatory properties of this hormone have been recognized only more recently. Vasopressin, a hormone best known for its anti-diuretic effect, also has anti-inflammatory actions. Surprisingly, vasopressin's close cousin, oxytocin, has broader and more potent anti-inflammatory effects than vasopressin and a larger number of pre-clinical studies supporting its potential role in limiting sepsis-associated organ damage. This review explores possible links between oxytocin and related octapeptide hormones and sepsis-related modulation of pro-inflammatory and anti-inflammatory activities.

Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice.

Obesity, a serious and growing health threat, is associated with low-grade inflammation that plays a role in mediating its adverse consequences. Previously, we have discovered a role for neural cholinergic signaling in controlling inflammation, and demonstrated that the cholinergic agent galantamine suppresses excessive proinflammatory cytokine release. The main objective of this study was to examine the efficacy of galantamine, a clinically-approved drug, in alleviating obesity-related inflammation and associated complications. After 8 wks on a high-fat diet, C57BL/6J mice were treated with either galantamine (4 mg/kg, intraperitoneally [i.p.]) or saline for 4 wks in parallel with mice on a low-fat diet and treated with saline. Galantamine treatment of obese mice significantly reduced body weight, food intake, abdominal adiposity, plasma cytokine and adipokine levels, and significantly improved blood glucose, insulin resistance and hepatic steatosis. In addition, galantamine alleviated impaired insulin sensitivity and glucose intolerance significantly. These results indicate a previously unrecognized potential of galantamine in alleviating obesity, inflammation and other obesity-related complications in mice. These findings are of interest for studying the efficacy of this clinically-approved drug in the context of human obesity and metabolic syndrome.