Obesity: a gender-view.

PURPOSE: There is a growing awareness of the importance of understanding gender differences in obesity. The aim of this short review was to revise the current evidence on anthropometric characteristics and nutritional and pharmacological aspects of obesity from a gender perspective. METHODS: A literature search within PubMed was performed. Selected publications related to obesity and gender differences were reviewed. RESULTS: The prevalence of obesity among men is higher than in women, but women have a higher percentage of body fat content compared to men, and gender appears to be an important factor in the manifestation of central (android) or peripheral (gynoid) obesity. In addition, while in most clinical trials, women are still underrepresented, in clinical registration trials of anti-obesity drugs, women are commonly up-represented and gender-specific analysis is uncommon. Considering that adipose tissue is one of the factors affecting the volume of distribution of many drugs, mainly lipophilic drugs, gender differences might be expected in the pharmacokinetics and pharmacodynamics of anti-obesity drugs. Indeed, although Liraglutide 3 mg, a long-acting glucagon-like peptide-1 receptor agonist, and naltrexone/bupropion display lipophilic properties, currently, a gender-dose adjustment for both these drugs administration is not recommended. In addition, despite that predicted responders to treatment offer substantial opportunities for efficient use, especially of expensive new therapies, such as anti-obesity drugs, data on gender differences to identify early responders to both these have not yet been investigated. Finally, bariatric surgery gender disparity reflects healthcare practices. Weight loss similar, but differing effects: women need more correction and face psychology challenges; men have worse physiology and fewer comorbidity improvements. CONCLUSION: Gender differences exist in obesity prevalence and phenotype, body fat distribution, drug efficacy, clinical trial representation, and different secondary effects of bariatric surgery. Gender is an important variable in obesity analysis.

Role of Mediterranean diet in endocrine diseases: a joint overview by the endocrinologist and the nutritionist.

PURPOSE: The purpose of this review is to examine the current evidence on the potential role of Mediterranean diet (MD) in the prevention and management of endocrine disorders and to highlight the importance of interdisciplinary collaboration between endocrinologists and nutritionists. METHODS: A literature search was conducted using PubMed and Google Scholar databases to identify relevant studies published in English. Studies were selected based on their relevance to the role of MD in the prevention and management of endocrine disorders. The search terms included "Mediterranean diet," "endocrine disorders," "thyroid disorders," "gonadal disorders," and "neuroendocrine tumors". RESULTS: The studies reviewed suggest that MD may have a beneficial effect in the prevention and management of various endocrine disorders, including thyroid disorders, gonadal disorders, and neuroendocrine tumors. MD has been associated with decreased risk of nodular thyroid disease and thyroid cancer, improved male and female reproductive health, and a potential role in the management of neuroendocrine tumors. MD's anti-inflammatory and antioxidant properties, as well as its high levels of phytochemicals, may play a role in its beneficial effects. CONCLUSION: Interdisciplinary collaboration between endocrinologists and nutritionists is essential for the optimal management of endocrine disorders, including the potential role of MD in their prevention and management. While further research is needed, the current evidence suggests that MD may have a protective effect against endocrine disorders, and its incorporation into dietary recommendations may be beneficial.

Ketogenic nutritional therapy (KeNuT)-a multi-step dietary model with meal replacements for the management of obesity and its related metabolic disorders: a consensus statement from the working group of the Club of the Italian Society of Endocrinology (SIE)-diet therapies in endocrinology and metabolism.

PURPOSE: The ketogenic nutritional therapy (KeNuT) is an effective dietary treatment for patients with obesity and obesity-related comorbidities, including type 2 diabetes, dyslipidaemia, hypertension, coronary artery disease, and some type of cancers. However, to date an official document on the correct prescription of the ketogenic diet, validated by authoritative societies in nutrition or endocrine sciences, is missing. It is important to emphasize that the ketogenic nutritional therapy requires proper medical supervision for patient selection, due to the complex biochemical implications of ketosis and the need for a strict therapeutic compliance, and an experienced nutritionist for proper personalization of the whole nutritional protocol. METHODS: This practical guide provides an update of main clinical indications and contraindications of ketogenic nutritional therapy with meal replacements and its mechanisms of action. In addition, the various phases of the protocol involving meal replacements, its monitoring, clinical management and potential side effects, are also discussed. CONCLUSION: This practical guide will help the healthcare provider to acquire the necessary skills to provide a comprehensive care of patients with overweight, obesity and obesity-related diseases, using a multistep ketogenic dietary treatment, recognized by the Club of the Italian Society of Endocrinology (SIE)-Diet Therapies in Endocrinology and Metabolism.

Vitamin D and chronotype: is there any relationship in individuals with obesity?

PURPOSE: Chronotype is the attitude to perform most of the daily activities in the morning ("morning chronotype", MC) or in the evening ("evening chronotype", EC). The latter, as well as vitamin D deficiency, has been associated with an increased risk of obesity-related complications, likely through the promotion of insulin resistance. Therefore, we aimed to investigate whether there is any relationship between vitamin D (25-OH-D) and chronotype in individuals with obesity. METHODS: In this cross-sectional study, we enrolled 59 individuals (43.1 ± 13 years; 17M/42F) with obesity. Anthropometric parameters, lifestyle habits, personal medical history, chronotype, insulin resistance, and 25-OH-D were assessed. RESULTS: Individuals with EC presented significantly higher BMI than MC (p < 0.001), greater waist (p = 0.012), and hip circumferences (p = 0.001). Individuals with EC showed significantly lower insulin sensitivity (p = 0.017) and 25-OH-D than MC. In addition, the prevalence of vitamin D deficiency and impaired fasting glucose was significantly higher in EC than in MC. 25-OH-D directly correlated with chronotype score (r = 0.351; p = 0.019) whereas inversely with BMI (r = - 0.363; p = 0.016). The regression analysis showed that BMI was most tightly associated with 25-OH-D concentrations (ß = - 0.323, p = 0.032), followed by chronotype score (ß = 0.340, p = 0.042). Using chronotype score as the dependent variable, BMI significantly predicted a lower chronotype score (ß = - 0.586, p < 0.001). CONCLUSION: The present study showed that 25-OH-D, as well as chronotype, correlate independently with obesity.

Weight stigma speaks Italian, too.

PURPOSE: Weight stigma is the negative weight related attitudes and beliefs towards individuals because of their overweight or obesity. Subjects with obesity are often victim of weight-related stigma resulting in a significant negative social consequence. As obesity epidemic is growing so fast, there is urgency to act on weight-stigma related social consequences being potentially serious and pervasive. This study investigated experiences, interpersonal sources, and context of weight stigma in Italy in a sample of adult subjects with obesity. METHODS: An online questionnaire was distributed to respondents via a snowball sampling method among subjects with obesity belonging to Italian Associations for people living with obesity aged 18 years and above. RESULTS: Four hundred and three respondents (47.18 ± 9.44 years; body mass index (BMI) 33.2 ± 8.48 kg/m2) participated to the study. Most respondents were females (94.8%). The age first dieted was 15.82 ± 7.12 years. The mean period of obesity was 27.49 ± 11.41 years. Frequency analyses reported that stigmatizing situations were experienced by 98% of participants: 94.82% during adulthood, 89.88% during adolescence and 75.39% during childhood. Verbal mistreatments (92.43%) was the most reported stigmatizing situation, strangers (92.43%) were the most common interpersonal sources of stigma and public settings (88.08%) were the most common location of stigma. CONCLUSIONS: Identifying strategies acting on the identified weight stigma targets could contribute to reduce weight stigma and thus to result in important implications for obesity treatment in Italy.

Liraglutide and polycystic ovary syndrome: is it only a matter of body weight?

Despite Polycystic Ovary Syndrome (PCOS) is a very prevalent disorder among women of reproductive age, there is widespread agreement that until now, no pharmacological options are available to tackle the entire spectrum of clinical manifestations encountered in the clinical practice. Obesity and insulin resistance, which commonly characterized this syndrome, prompted the design of studies investigating the effects of glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) in PCOS. Indeed, a very impressive number of randomized controlled clinical trials (RCTs) and systematic reviews provided robust evidence on the effectiveness of GLP-1RA in PCOS as a new, appealing approach, producing both satisfactory and permanent weight loss, and improvement of insulin resistance at the same time. However, most of the subjects included in the RCTs are PCOS patients with obesity/overweight, whereas a portion of PCOS women, which can even reach 50%, might present a lean phenotype. Moreover, some benefits on clinical and metabolic features of PCOS may not have fully emerged due to the low or medium doses employed in the vast majority of the current studies. Thus, pitfalls in the methodology of these studies have led sometimes to misleading results. In addition, some aspects of GLP-1 beyond weight loss, such as preclinical evidence on GLP-1 effects in directly modulating the hypothalamus-pituitary-gonadal axis, or the effects of GLP-1RA on clinical and biochemical expression of hyperandrogenism, still deserve a greater insight, especially in light of a possible therapeutic use in PCOS women independently of obesity. Aim of this review is to further unravel the possible role of GLP-1 in PCOS pathogenesis, tempting to provide additional supports to the rationale of treatment with GLP-1RA in the management of PCOS also independent of weight loss. For this purpose, the outcomes of RCTs investigating in PCOS the anthropometric and metabolic changes have been treated separately to better underpin the effects of GLP-1 RA, in particular liraglutide, beyond weight loss.

Effects of very low-calorie ketogenic diet on hypothalamic-pituitary-adrenal axis and renin-angiotensin-aldosterone system.

BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system involved in controlling stress responses in humans under physiological and pathological conditions; cortisol is the main hormone produced by the HPA axis. It is known that calorie restriction acts as a stressor and can lead to an increase in cortisol production. Renin-angiotensin-aldosterone system (RAAS) is a complex endocrine network regulating blood pressure and hydrosaline metabolism, whose final hormonal effector is aldosterone. RAAS activation is linked to cardiometabolic diseases, such as heart failure and obesity. Obesity has become a leading worldwide pandemic, associated with serious health outcomes. Calorie restriction represents a pivotal strategy to tackle obesity. On the other hand, it is well known that an increased activity of the HPA may favour visceral adipose tissue expansion, which may jeopardize a successful diet-induced weight loss. Very low-calorie ketogenic diet (VLCKD) is a normoprotein diet with a drastic reduction of the carbohydrate content and total calorie intake. Thanks to its sustained protein content, VLCKD is extremely effective to reduce adipose tissue while preserving lean body mass and resting metabolic rate. PURPOSE: The purpose of this narrative review is to gain more insights on the effects of VLCKD on the HPA axis and RAAS, in different phases of weight loss and in different clinical settings.

Body composition and obstructive sleep apnoea assessment in adult patients with Prader-Willi syndrome: a case control study.

INTRODUCTION: In Prader-Willi syndrome (PWS) adult patients, sleep-breathing disorders, especially obstructive sleep apnoea syndrome (OSAS), are very common, whose missed or delayed diagnosis can contribute to further increase cardiovascular morbidity and mortality. PURPOSE: The aim of this cross-sectional study was to evaluate differences in sleep-breathing parameters obtained by overnight cardiorespiratory polygraphy in 13 adult PWS patients and 13 individuals with non-syndromic obesity as controls matched by age, sex, and BMI. METHODS: In all subjects' anthropometric parameters, body composition using bioimpedance analysis and overnight cardiorespiratory monitoring parameters were obtained. RESULTS: Ten (76.9%) PWS patients were diagnosed with OSAS, most notably nine (69.2%) and one PWS (7.7%) with mild and severe OSAS, respectively. Compared with the control group, PWS patients had evidence of higher apnoea-hypopnea index (AHI) (p = 0.04) and oxyhaemoglobin desaturation index (ODI) (p = 0.009). However, no differences were found between the two groups regarding OSAS categories or diagnosis of nocturnal respiratory failure. In the PWS group, there were no significant correlations among AHI, ODI and hypoxemia index (T90) and anthropometric measurements, fat mass (FM), and FM percentage (%). Conversely, in the control group, the sleep-related respiratory indices evaluated correlated positively with BMI, waist circumference, FM and FM%. CONCLUSIONS: This study confirmed that AHI and ODI indices were worse in PWS than in age, sex and BMI-matched controls. The lack of their significant association with the anthropometric parameters and FM supported the existence of PWS-related mechanisms in OSAS pathophysiology that are independent of visceral obesity and FM.

Obesity in Prader-Willi syndrome: physiopathological mechanisms, nutritional and pharmacological approaches.

Prader-Willi syndrome (PWS) is a genetic disorder caused by the lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. The three main genetic subtypes are represented by paternal 15q11-q13 deletion, maternal uniparental disomy 15, and imprinting defect. Clinical picture of PWS changes across life stages. The main clinical characteristics are represented by short stature, developmental delay, cognitive disability and behavioral diseases. Hypotonia and poor suck resulting in failure to thrive are typical of infancy. As the subjects with PWS age, clinical manifestations such as hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency due to hypothalamic dysfunction occur. Obesity and its complications are the most common causes of morbidity and mortality in PWS. Several mechanisms for the aetiology of obesity in PWS have been hypothesized, which include aberration in hypothalamic pathways of satiety control resulting in hyperphagia, disruption in hormones regulating appetite and satiety and reduced energy expenditure. However, despite the advancement in the research field of the genetic basis of obesity in PWS, there are contradictory data on the management. Although it is mandatory to adopt obesity strategy prevention from infancy, there is promising evidence regarding the management of obesity in adulthood with current obesity drugs along with lifestyle interventions, although the data are limited. Therefore, the current manuscript provides a review of the current evidence on obesity and PWS, covering physiopathological aspects, obesity-related complications and conservative management.

Oral contraceptives versus physical exercise on cardiovascular and metabolic risk factors in women with polycystic ovary syndrome: a randomized controlled trial.

BACKGROUND: Although oral contraceptives (OCs) are one the most widespread therapy in young polycystic ovary syndrome (PCOS) women and physical exercise represents a crucial first step in the treatment of overweight and obese PCOS, no studies were performed to compare the effects on cardiovascular risk (CVR) of OCs and physical exercise in PCOS. OBJECTIVE: To compare the effects of OCs administration and physical exercise on the CVR, clinical, hormonal and metabolic parameters in PCOS women. METHODS: One hundred and fifty PCOS women were enrolled and were randomized to OCs (3 mg drospirenone plus 30 µg ethinyloestradiol), structured exercise training programme (SETP) or polyvitamin tablets. The intervention phase study was of 6 months. Primary outcome was intima-media thickness (IMT) and flow-mediated dilation (FMD). Secondary outcomes were clinical, hormonal and metabolic changes. RESULTS: A significant reduction of IMT and a significant increase of FMD were observed in the SETP group after treatment. Compared to baseline, in the SETP group, a significant improvement in anthropometric measures, insulin sensitivity indexes, lipid profile, cardiopulmonary function, inflammatory markers and frequency of menses was observed. Oral contraceptives use was associated with a significant decrease of hyperandrogenism and a significant improvement of frequency of menses. Further, OCs use had a neutral effect on CVR risk factors. CONCLUSION: OCs effectively treat hyperandrogenism and menstrual disturbances, while SETP is more effective in improving cardiometabolic profile and cardiopulmonary function in PCOS.

Focus on vitamin D and the adrenal gland.

The main role of vitamin D is to maintain calcium and phosphorus homeostasis, thus preserving bone health. However, recent evidences have demonstrated that vitamin D may also play a role in a variety of nonskeletal disorders such as endocrine diseases and in particular type 1 diabetes, type 2 diabetes, adrenal diseases, and the polycystic ovary syndrome. Despite controversial results on an association of low vitamin D levels with cortisol and aldosterone overproduction, encouraging in vitro findings have been reported on vitamin D effects in adrenocortical cancer cells. The focus of this review is the role of vitamin D in adrenal diseases and the results of vitamin D supplementation studies in patients. Although many studies support a beneficial role of vitamin D in adrenal disease, randomized controlled trials and mechanistic studies are required to provide more insight into the efficacy and safety of vitamin D as a therapeutic tool.

GLP-1: benefits beyond pancreas.

INTRODUCTION: Glucagon-like peptide 1 (GLP-1) is an intestinal hormone secreted after the ingestion of various nutrients. The main role of GLP-1 is to stimulate insulin secretion in a glucose-dependent manner. However, the expression of GLP-1 receptor was found to be expressed in a variety of tissues beyond pancreas such as lung, stomach, intestine, kidney, heart and brain. Beyond pancreas, a beneficial effect of GLP-1 on body weight reduction has been shown, suggesting its role for the treatment of obesity. In addition, GLP-1 has been demonstrated to reduce cardiovascular risk factors and to have a direct cardioprotective effect, fostering heart recovery after ischemic injury. Further, data from both experimental animal models and human studies have shown beneficial effect of GLP-1 on bone metabolism, either directly or indirectly on bone cells. MATERIALS AND METHODS: We review here the recent findings of the extra-pancreatic effects of GLP-1 focusing on both basic and clinical studies, thus opening future perspectives to the use of GLP-1 analogs for the treatment of disease beyond type 2 diabetes. CONCLUSION: Finally, the GLP-1 has been demonstrated to have a beneficial effect on both vascular, degenerative diseases of central nervous system and psoriasis.

Effects of physical exercise on the female reproductive system.

The excess in physical activity could be closely linked to considerable negative consequences on the whole body. These dysfunctions called as "female athlete triad"' by the American College of Sports Medicine (ACSM) include amenorrhea, osteoporosis and disorder eating. The female athlete triad poses serious health risks, both on the short and on the long term, to the overall well-being of affected individuals. Sustained low energy availability can impair health, causing many medical complications within skeletal, endocrine, cardiovascular, reproductive and central nervous system. On the contrary, several studies have shown, that physical activity improves cardiovascular risk factors, hormonal profile and reproductive function. These improvements include a decrease in abdominal fat, blood glucose, blood lipids and insulin resistance, as well as improvements in menstrual cyclicity, ovulation and fertility, decreases in testosterone levels and Free Androgen Index (FAI) and increases in sex hormone binding globulin (SHBG). Other studies reported that physical activity improved self-esteem, depression and anxiety. Thus, the aim of this review is to elucidate the effect of physical exercise on female reproductive system and viceversa the impact of hormonal status on physical activity and metabolism. In addition this review supports the idea that physical exercise is a helpful tool for the management of obesity, prevention of cardiovascular, metabolic diseases and female reproductive organs related diseases (e.g. breast cancer). When the excess in physical activity leads up to the female athlete triad, it is imperative to treat each component of the triad by employing both pharmacological and non pharmacological treatments.

Bariatric surgery and bone disease: from clinical perspective to molecular insights.

The use of bariatric surgery for the treatment of morbid obesity has increased annually for the last decade. Although many studies have demonstrated the efficacy and durability of bariatric surgery for weight loss, there are limited data regarding long-term side effects of these procedures. Recently, there has been an increased focus on the impact of bariatric surgery on bone metabolism. Bariatric surgery utilizes one or more of three mechanisms of action resulting in sustained weight loss. These include restriction (gastric banding, vertical banded gastroplasty and sleeve gastrectomy), malabsorption surgery with or without associated restriction (Roux en Y gastric bypass, duodenal switch, biliopancreatic diversion and jejunoileal bypass) and changes in gut-derived hormones that control energy metabolism also referred to as neuro-hormonal control of energy metabolism (Roux en Y gastric bypass, duodenal switch, biliopancreatic diversion, jejunoileal bypass, surgical procedures as above and gastric sleeve). Weight reduction has been associated with increased bone resorption but the mechanisms behind this have not yet been fully elucidated. Each of the mechanisms of action of bariatric surgery (restriction, malabsorption, neuro-hormonal control of energy metabolism) may uniquely affect bone resorption. In this paper we will review the current state of knowledge regarding the relationship between bariatric surgery and bone metabolism with emphasis on possible mechanisms of action such as malnutrition, hormonal interactions and mechanical unloading of the skeleton. Further, we suggest a future research agenda.

Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives.

Several studies have shown that vitamin D may play a role in many biochemical mechanisms in addition to bone and calcium metabolism. Recently, vitamin D has sparked widespread interest because of its involvement in the homeostasis of the cardiovascular system. Hypovitaminosis D has been associated with obesity, related to trapping in adipose tissue due to its lipophilic structure. In addition, vitamin D deficiency is associated with increased risk of cardiovascular disease (CVD) and this may be due to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which it might modulate cardiovascular risk are not fully understood. Given this background, in this work we summarise clinical retrospective and prospective observational studies linking vitamin D levels with cardio-metabolic risk factors and vascular outcome. Moreover, we review various randomised controlled trials (RCTs) investigating the effects of vitamin D supplementation on surrogate markers of cardiovascular risk. Considering the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D replacement therapy in this population may be warranted; however, further RCTs are urgently needed to establish when to begin vitamin D therapy, as well as to determine the dose and route and duration of administration.

Metabolic syndrome in transplant patients: an updating point of view.

Metabolic syndrome (MS) is a cluster of risk factors that predispose to major cardiovascular diseases and its complications, determining liver and kidney impairment. In the last decade, the indications to transplantation are increasing, with a linear incidence of the complications of the procedure. MS represents one of the commonest, being in turn may the consequence of the underlying disease that required the transplantation, or the result of the medical treatment, as well as one of the most important factor influencing the morbidity and mortality of the transplanted patients. Due to the growing incidence of the MS in these patients, it is crucial to focus and clarify the leading causes determining the onset of the metabolic disarrangement, its outcome and the hypothetical mechanism through which the clinicians could reduce the impact of the disease. In fact, prevention, early recognition, and treatment of the factor that could predict the onset or progression of the MS after the transplantation may impact long term survival of patients, that is again the scope of the same transplant. This review will update the different mechanisMS of the pathogenesis of MS in this population, the clinical effects of the presence of the MS, observing the risk factors to be treated before and after the transplantation and suggesting the management of the follow-up.

Vitamin D deficiency: a new risk factor for type 2 diabetes?.

Recent compelling evidence suggests a role of vitamin D deficiency in the pathogenesis of insulin resistance and insulin secretion derangements, with a consequent possible interference with type 2 diabetes mellitus. The mechanism of this link is incompletely understood. In fact, vitamin D deficiency is usually detected in obesity in which insulin resistance is also a common finding. The coexistence of insulin resistance and vitamin D deficiency has generated several hypotheses. Some cross-sectional and prospective studies have suggested that vitamin D deficiency may play a role in worsening insulin resistance; others have identified obesity as a risk factor predisposing individuals to exhibit both vitamin D deficiency and insulin resistance. The available data from intervention studies are largely confounded, and inadequate considerations of seasonal effects on 25(OH)D concentrations are also a common design flaw in many studies. On the contrary, there is strong evidence that obesity might cause both vitamin D deficiency and insulin resistance, leaving open the possibility that vitamin D and diabetes are not related at all. Although it might seem premature to draw firm conclusions on the role of vitamin D supplementation in reducing insulin resistance and preventing type 2 diabetes, this manuscript will review the circumstances leading to vitamin D deficiency and how such a deficiency can eventually independently affect insulin sensitivity.

Dual source CT: state of the art in the depiction of coronary arteries anatomy, anatomical variants and myocardial segments.

Cardiovascular disease is the leading cause of death in adults in western countries. Coronary angiography remains the gold standard for the diagnosis of coronary artery disease, a procedure that carries risks. Nowadays, a significant number of the coronary angiographies performed every year are only diagnostic. Multidetector computed tomography (MDCT) allows non-invasive evaluation of coronary arteries. It is a continuously developing technique, and actually the top technology is represented by Dual Source CT. This scanner of new conception permits an improvement in image quality, and visualization of distal vessels and small collateral branches. The aim of our work is to illustrate the actual state of the art in non-invasive coronary arteries evaluation represented by Dual Source CT, presenting images of coronary arteries normal anatomy, anatomical variants and myocardial segment.

Critical role of chemokine (C-C motif) receptor 2 (CCR2) in the KKAy + Apoe -/- mouse model of the metabolic syndrome.

AIMS/HYPOTHESIS: Chemokines and their receptors such as chemokine (C-C motif) receptor 2 (CCR2) may contribute to the pathogenesis of the metabolic syndrome via their effects on inflammatory monocytes. Increased accumulation of CCR2-driven inflammatory monocytes in epididymal fat pads is thought to favour the development of insulin resistance. Ultimately, the resulting hyperglycaemia and dyslipidaemia contribute to development of the metabolic syndrome complications such as cardiovascular disease and diabetic nephropathy. Our goal was to elucidate the role of CCR2 and inflammatory monocytes in a mouse model that resembles the human metabolic syndrome. METHODS: We generated a model of the metabolic syndrome by backcrossing KKAy ( + ) with Apoe ( -/- ) mice (KKAy ( + ) Apoe ( -/- )) and studied the role of CCR2 in this model system. RESULTS: KKAy ( + ) Apoe ( -/- ) mice were characterised by the presence of obesity, insulin resistance, dyslipidaemia and increased systemic inflammation. This model also manifested two complications of the metabolic syndrome: atherosclerosis and diabetic nephropathy. Inactivation of Ccr2 in KKAy (+) Apoe ( -/- ) mice protected against the metabolic syndrome, as well as atherosclerosis and diabetic nephropathy. This protective phenotype was associated with a reduced number of inflammatory monocytes in the liver and muscle, but not in the epididymal fat pads; circulating levels of adipokines such as leptin, resistin and adiponectin were also not reduced. Interestingly, the proportion of inflammatory monocytes in the liver, pancreas and muscle, but not in the epididymal fat pads, correlated significantly with peripheral glucose levels. CONCLUSIONS/INTERPRETATION: CCR2-driven inflammatory monocyte accumulation in the liver and muscle may be a critical pathogenic factor in the development of the metabolic syndrome.