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Background/objectives: Dieting is a popular yet often ineffective way to lower body weight, as the majority of people regain most of their pre-dieting weights in a relatively short time. The underlying molecular mechanisms driving weight regain and the increased risk for metabolic disease are still incompletely understood. Here we investigate the molecular alterations inherited from a history of obesity., Methods: In our model, male high-fat diet (HFD)-fed obese C57BL/6J mice were switched to a low caloric chow diet, resulting in a decline of body weight to that of lean mice. We measured body composition, as well as metrics of glucose, insulin and lipid homeostasis. This was accompanied by histological and gene expression analysis of adipose tissue and liver to assess adipose tissue inflammation and hepatosteatosis. Moreover, acute hypothalamic response to (re-) exposure to HFD was assessed by qPCR., Results & Conclusions: Within 7 weeks after diet switch, most obesity-associated phenotypes, such as body mass, glucose intolerance and blood metabolite levels were reversed. However, hepatic inflammation, hepatic steatosis as well as hypertrophy and inflammation of perigonadal, but not subcutaneous, adipocytes persisted in formerly obese mice. Transcriptional profiling of liver and perigonadal fat revealed an upregulation of pathways associated with immune function and cellularity. Thus, we show that weight reduction leaves signs of inflammation in liver and perigonadal fat, indicating that persisting proinflammatory signals in liver and adipose tissue could contribute to an increased risk of formerly obese subjects to develop the metabolic syndrome upon recurring weight gain.

Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Hypothalamic inflammation is a potentially important process in the pathogenesis of high-fat diet-induced metabolic disorders that has recently received significant attention. Microglia are macrophage-like cells of the central nervous system which are activated by pro-inflammatory signals causing local production of specific interleukins and cytokines, and these in turn may further promote systemic metabolic disease. Whether or how this microglial activation can be averted or reversed is unknown. Since running exercise improves systemic metabolic health and has been found to promote neuronal survival as well as the recovery of brain functions after injury, we hypothesized that regular treadmill running may blunt the effect of western diet on hypothalamic inflammation. Using low-density lipoprotein receptor deficient (l dlr-/-) mice to better reflect human lipid metabolism, we first confirmed that microglial activation in the hypothalamus is severely increased upon exposure to a high-fat, or "western", diet. Moderate, but regular, treadmill running exercise markedly decreased hypothalamic inflammation in these mice. Furthermore, the observed decline in microglial activation was associated with an improvement of glucose tolerance. Our findings support the hypothesis that hypothalamic inflammation can be reversed by exercise and suggest that interventions to avert or reverse neuronal damage may offer relevant potential in obesity treatment and prevention., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Obesity-induced inflammation is critical for the development of insulin resistance. Here, we show that genetic inactivation of PKCzeta in vivo leads to a hyperinflammatory state in obese mice that correlates with a higher glucose intolerance and insulin resistance. Previous studies implicated PKCzeta in the regulation of type 2 inflammatory responses in T cells. By using ex vivo and in vivo experiments, we demonstrate that although PKCzeta is involved in the alternative (M2) activation of macrophages, surprisingly, PKCzeta ablation in the nonhematopoietic compartment but not in the hematopoietic system is sufficient to drive inflammation and IL-6 synthesis in the adipose tissue, as well as insulin resistance. Experiments using PKCzeta/IL-6 double-knockout mice demonstrated that IL-6 production accounts for obesity-associated glucose intolerance induced by PKCzeta deficiency. These results establish PKCzeta as a critical negative regulator of IL-6 in the control of obesity-induced inflammation in adipocytes., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Multiple pathways contribute to accelerated coronary atherosclerosis in diabetics, including increased oxidative stress and inflammatory burden. Accordingly, the mechanisms of abnormal formation of reactive oxygen species and the changes in inflammatory gene expression were examined in diabetic coronary arteries., Methods and Results: In pigs with streptozotocin-induced diabetes, superoxide formation was augmented in coronary media and adventitia because of increased NAD(P)H oxidase activity (3 months) accompanied by upregulated expression of its cytosolic subunit, p22phox. Diabetes-induced oxidative stress resulted in the inflammatory response in the adventitia (increased expression of interleukin-6, tumor necrosis factor-alpha, monocyte chemotactic protein-1, vascular cell adhesion molecule-1 [VCAM-1]) and in the media (VCAM-1). To examine the mechanisms of these changes, studies with isolated coronary fibroblasts were undertaken. Advanced glycation end products (AGEs), rather than glucose itself, upregulated expression of interleukin-6, VCAM-1, and monocyte chemotactic protein-1 mRNAs. These results were paralleled by increased interleukin-6 secretion (P<0.01) and augmented leukocyte adhesion to AGE-stimulated coronary cells (P<0.001). AGEs increased expression of phosphorylated forms of mitogen-activated protein kinases in coronary cells (ERK1/2 and JNK) and resulted in redox-sensitive expression of inflammatory genes that was inhibited by several inhibitors of oxidative pathways [NAD(P)H oxidase inhibitors, N-acetylcysteine, and pyrrolidine dithiocarbamate]., Conclusions: Diabetes increased NAD(P)H oxidase activity and oxidative stress, producing inflammatory responses in porcine coronary media and adventitia. AGEs activated ERK1/2 and JNK signaling pathways and induced the expression of several inflammatory genes in coronary cells in a redox-sensitive manner. These results suggest the involvement of AGEs in the development of accelerated coronary atherosclerosis in diabetes.