The link between obesity and autoimmunity.

Overnutrition could lead to loss of self-tolerance by impinging on immune regulation.

Inflammatory domains modulate autism spectrum disorder susceptibility during maternal nutritional programming.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease which involves functional and structural defects in selective central nervous system (CNS) regions harming capability to process and respond to external stimuli. In addition to genetic background, etiological causes of ASD have not been fully clarified. Maternal immune activation (MIA) during pregnancy have been proposed as a potential etiological cause leading to aberrant synaptic pruning and microglia-mediated neurogenesis impairment. Several clinical studies suggest that pro-inflammatory profile during maternal obesity associates with a higher risk of having a child with autism. In this context, the effect of maternal programing by high fat diet overconsumption during pregnancy sets a pro-inflammatory profile partly dependent on an epigenetic program of immunity which promotes brain micro and macrostructural abnormalities in the offspring that might last through adulthood accompanied by phenotypic changes in ASD subjects. Of note, maternal programming of inflammation during development seems to integrate the CNS and peripheral immune system cross-talk which arrays central inflammatory domains coordinating ASD behavior. In this review, we discuss basic and clinical studies regarding the effects of obesity-induced MIA on peripheral immune cells and microglia priming and their relationship with brain structural alterations in ASD models. Also, we show supportive evidence stating the role of maternal programming on epigenetic gene activation in immune cells of ASD subjects. We suggest that maternal programming by hypercaloric diets during development sets a central and peripheral immune cross-talk which potentially might modulate brain macro and microstructural defects leading to autism susceptibility.

Adapting to obesity with adipose tissue inflammation.

Adipose tissue not only has an important role in the storage of excess nutrients but also senses nutrient status and regulates energy mobilization. An overall positive energy balance is associated with overnutrition and leads to excessive accumulation of fat in adipocytes. These cells respond by initiating an inflammatory response that, although maladaptive in the long run, might initially be a physiological response to the stresses obesity places on adipose tissue. In this Review, we characterize adipose tissue inflammation and review the current knowledge of what triggers obesity-associated inflammation in adipose tissue. We examine the connection between adipose tissue inflammation and the development of insulin resistance and catecholamine resistance and discuss the ensuing state of metabolic inflexibility. Finally, we review the current and potential new anti-inflammatory treatments for obesity-associated metabolic disease.

Nutrition, inflammation and cancer.

Quantitative and qualitative aspects of nutrition have a profound effect on leukocytes and thereby affect proinflammatory carcinogenic effects or anticancer immune responses. As a result, nutrition affects the incidence, natural progression and therapeutic response of malignant diseases, both in humans and in preclinical animal models. Here we discuss the molecular mechanisms through which alimentary cues modulate metabolic, microbial and neuroendocrine circuitries and thus affect the probability of developing premalignant lesions that progress to clinically manifested disease and the response to therapeutic intervention. We examine each of the connections that compose the triangle of nutrition, immunological and inflammatory reactions and cancer while focusing on the mechanistic aspects of these relationships.

Neuroinflammatory and autonomic mechanisms in diabetes and hypertension.

Interdisciplinary studies in the research fields of endocrinology and immunology show that obesity-associated overnutrition leads to neuroinflammatory molecular changes, in particular in the hypothalamus, chronically causing various disorders known as elements of metabolic syndrome. In this process, neural or hypothalamic inflammation impairs the neuroendocrine and autonomic regulation of the brain over blood pressure and glucose homeostasis as well as insulin secretion, and elevated sympathetic activation has been appreciated as a critical mediator. This review describes the involved physiology and mechanisms, with a focus on glucose and blood pressure balance, and suggests that neuroinflammation employs the autonomic nervous system to mediate the development of diabetes and hypertension.

The manner of the inflammation-boosting effect caused by acute hyperglycemia secondary to overfeeding and the effects of insulin therapy in a rat model of sepsis.

BACKGROUND: The aim of the study was to investigate both the inflammation-boosting effect and the metabolic stress induced by acute hyperglycemia secondary to overfeeding with excessive glucose infusion and the effects of insulin therapy on those events in a rat model of sepsis. MATERIALS AND METHODS: Sprague-Dawley rats underwent cecal ligation and puncture (CLP) or sham operation. Preestablished continuous intravenous glucose infusion was initiated immediately after surgery. First, rats with CLP-inducing sepsis were divided into three groups on the basis of the target blood glucose (BG) levels: high glucose (HG) group (overfed, >300 mg/dL), moderate glucose group (moderate hyperglycemia, 200-300 mg/dL), and no glucose group (100-150 mg/dL). The sham group received the same glucose infusion as that of the HG group. BG and plasma interleukin (IL) 6 levels were monitored over time. All rats were sacrificed 9 h after surgery to evaluate lung histology and measure hepatic total glutathione and malondialdehyde contents. Based on the results, the high glucose and insulin (HI) group was added to septic groups as a model of insulin therapy, in which insulin with the same HG dose as that in the HG group was administered to maintain moderate hyperglycemia. RESULTS: BG level in all groups remained in the preestablished target range throughout the experiment. Plasma IL-6 level in all septic groups increased in a time-dependent manner, whereas that in the sham group with moderate hyperglycemia hardly increased. Nine hours after CLP, plasma IL-6 level in the HG group rose to 7407.5 ± 1987.3 pg/mL, which was three times higher than that in the other septic groups. There was no significant difference among moderate glucose, no glucose, and HI groups, in which BG level remained constant at <300 mg/dL. The HG group showed the worst consequences of lung injury and oxidative stress in the liver, which were completely stable in HI group. CONCLUSIONS: Acute severe hyperglycemia in critical illness might excessively boost the existing systemic inflammatory response in a threshold-based manner. Insulin therapy under overfeeding could strongly inhibit such a boosting effect and oxidative stress in the liver.

Nutritional status, genetic susceptibility, and insulin resistance--important precedents to atherosclerosis.

Atherosclerosis is a progressive disease that starts early in life and is manifested clinically as coronary artery disease (CAD), cerebrovascular disease, or peripheral artery disease. CAD remains the leading cause of morbidity and mortality in Western society despite the great advances made in understanding its underlying pathophysiology. The key risk factors associated with CAD include hypercholesterolemia, hypertension, poor diet, obesity, age, male gender, smoking, and physical inactivity. Genetics also play an important role that may interact with environmental factors, including diet, nutritional status, and physiological parameters. Furthermore, certain chronic inflammatory conditions also predispose to the development of CAD. The spiraling increase in obesity rates worldwide has made it more pertinent than ever before to understand the metabolic perturbations that link over nutrition to enhanced cardiovascular risk. Great breakthroughs have been made at the pharmacological level to manage CAD; statins and aspirin have revolutionized treatment of CAD and prolonged lifespan. Nonetheless, lifestyle intervention prior to clinical presentation of CAD symptoms would negate/delay the need for chronic pharmacotherapy in at-risk individuals which in turn would relieve healthcare systems of a costly burden. Throughout this review, we debate the relative impact of nutrition versus genetics in driving CAD. We will investigate how overnutrition affects adipose tissue biology and drives IR and will discuss the subsequent implications for the cardiovascular system. Furthermore, we will discuss how lifestyle interventions including diet modification and weight loss can improve both IR and metabolic dyslipidemia that is associated with obesity. We will conclude by delving into the concept that nutritional status interacts with genetic susceptibility, such that perhaps a more personalized nutrition approach may be more effective in determining diet-related risk as well as response to nutritional interventions.

Obesity, inflammation and the immune system.

Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations. This inflammatory state is reflected in increased circulating levels of pro-inflammatory proteins, and it occurs not only in adults but also in adolescents and children. The chronic inflammatory response has its origin in the links existing between the adipose tissue and the immune system. Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses. In addition, evidence has arisen that an altered immune function contributes to the pathogenesis of obesity. This review attempts to briefly comment on the various plausible explanations that have been proposed for the phenomenon: (1) the obesity-associated increase in the production of leptin (pro-inflammatory) and the reduction in adiponectin (anti-inflammatory) seem to affect the activation of immune cells; (2) NEFA can induce inflammation through various mechanisms (such as modulation of adipokine production or activation of Toll-like receptors); (3) nutrient excess and adipocyte expansion trigger endoplasmic reticulum stress; and (4) hypoxia occurring in hypertrophied adipose tissue stimulates the expression of inflammatory genes and activates immune cells. Interestingly, data suggest a greater impact of visceral adipose tissue and central obesity, rather than total body fat, on the inflammatory process. In summary, there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications.

Interaction of nutrition and infections globally: an overview.

The interaction of nutrition and infections is known by experience by generations of medical doctors. Before the era of antibiotics, diet was an integral part of the management of infections. Now, it is necessary to take a fresh look at this interaction as the understanding of immune response has expanded considerably. Comparatively little research has addressed the impact of nutrition interventions on the management of infectious diseases. Most observations of the interaction between nutrition and infections are epidemiological in character. This holds especially true for measles as well as for tuberculosis. In AIDS, the deterioration of the nutritional status is an indicator of disease progression. Infections in undernourished children are a common cause of death, and taking this finding into account helps to reduce the case fatality rate in severely malnourished patients. Regarding the immune response, cellular as well as soluble components are affected by deficiencies of single nutrients or general undernutrition. The immunosuppressive effect of undernutrition starts during intrauterine life already: maternal nutrition status has been shown to impact on immune function in adult animals. Recent research suggests that not only undernutrition but also caloric overnutrition impacts on immune response to infections and immunization. This is partly due to the chronic inflammatory activity of the adipose tissue and partly due to neuroendocrine alterations. Infectious diseases also impact on the nutritional status, either specifically or through unspecific mechanisms, such as anorexia, tachypnea, and vomiting.