Defective regulation of POMC precedes hypothalamic inflammation in diet-induced obesity

Souza, Gabriela de Nardi; Solon, Carina; Nascimento, Lucas F.; de-Lima-Júnior, José C.; Nogueira, Guilherme; Moura, Rodrigo Ferreira de; Rocha, Guilherme Z.; Fioravante, Milena; Bóbbo, Vanessa Cristina Dias; Morari, Joseane; Razolli, Daniela S.; Araujo, Eliana P.; Velloso, Lı́cio A.

doi:10.1038/srep29290

Cited by 56 publications

(56 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These suggest that under obese/diabetic condition the peripheral excessive nutrients and hormones (e.g., fatty acid, glucose, or leptin) may affect the hypothalamic environment. Studies have shown that obesity induces hypothalamic inflammation accompanied by neuronal damage [ 7 ], and this is implicated in leptin/insulin resistance, disrupted energy homeostasis, and neurodegenerative diseases [ 8 , 9 ]. Thus, factors controlling obesity-related deleterious hypothalamic inflammation may have the potential to protect against hypothalamic dysfunction and neuro-metabolic complications.…”

Section: Introductionmentioning

confidence: 99%

Quercetin Protects Obesity-Induced Hypothalamic Inflammation by Reducing Microglia-Mediated Inflammatory Responses via HO-1 Induction

Yang

Kim

et al. 2017

Nutrients

View full text Add to dashboard Cite

Obesity-induced hypothalamic inflammation is characterized by activation of microglia, which are resident macrophages of the central nervous system, and is implicated in the derangement of energy homeostasis, metabolic complications, and neurodegenerative diseases. Quercetin, a naturally occurring flavonoid, is known to protect against oxidative stress and inflammation-related metabolic complications. Here, we demonstrate that quercetin reduces obesity-induced hypothalamic inflammation by inhibiting microglia-mediated inflammatory responses, and the beneficial action of quercetin is associated with heme oxygenase (HO-1) induction. Quercetin markedly reduced the production of inflammatory mediators (monocyte chemoattractant protein (MCP)-1, interleukin (IL-6), IL-1β, nitric oxide) by microglia stimulated with saturated fatty acid palmitate and/or lipid-laden microglia-conditioned medium. Quercetin also upregulated the expression of HO-1 in palmitate-treated lipid-laden microglia, and the actions of quercetin against microglia activation accompanied by IκBα degradation were abolished by a HO-1 inhibitor. Moreover, quercetin supplementation reduced the levels of inflammatory cytokines and microglia activation markers in the hypothalamus of high fat diet (HFD)-fed obese mice, which was accompanied by upregulation of HO-1. These findings indicate that quercetin suppresses microglia-mediated inflammatory responses via the induction of HO-1, and hence protects against obesity-induced hypothalamic inflammation.

show abstract

Section: Introductionmentioning

confidence: 99%

Quercetin Protects Obesity-Induced Hypothalamic Inflammation by Reducing Microglia-Mediated Inflammatory Responses via HO-1 Induction

Yang

Kim

et al. 2017

Nutrients

View full text Add to dashboard Cite

show abstract

“…We have previously shown that, in contrast to OP mice, glucose tolerance is preserved in OR mice fed an HFD [ 9 ]. Here, we evaluated glucose tolerance in OR mice treated with the anti-LIF antibody in the hypothalamus.…”

Section: Resultsmentioning

confidence: 99%

“…For the experiments, mice were randomly divided into groups fed either chow or a HFD (composition of the diets is presented in Additional file 1 : Table S1). To identify OP and OR mice, we used a previously described protocol [ 9 ]. In short, 8-week-old male Swiss mice were fed a HFD for 24 h, and total caloric intake was recorded.…”

Section: Methodsmentioning

confidence: 99%

“…Here, we hypothesized that different landscapes of chemokines produced in the hypothalamus in response to dietary fats could play a role in the protection against or predisposition to obesity. To test this hypothesis, we initially evaluated the landscape of chemokine-related transcripts expressed in the hypothalamus of mice fed on a HFD, comparing obesity-prone (OP) versus obesity-resistant (OR) mice [ 9 ]. We found that leukemia inhibitory factor (LIF) was one of the transcripts with the greatest difference between the two groups, with high expression in the hypothalamus of OR and low expression in the hypothalamus of OP mice.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of hypothalamic leukemia inhibitory factor exacerbates diet-induced obesity phenotype

Fioravante¹,

Bombassaro²,

Ramalho³

et al. 2017

J Neuroinflammation

Self Cite

View full text Add to dashboard Cite

BackgroundThe consumption of large amounts of dietary fats can trigger an inflammatory response in the hypothalamus and contribute to the dysfunctional control of caloric intake and energy expenditure commonly present in obesity. The objective of this study was to identify chemokine-related transcripts that could be involved in the early stages of diet-induced hypothalamic inflammation.MethodsWe used immunoblot, PCR array, real-time PCR, immunofluorescence staining, glucose and insulin tolerance tests, and determination of general metabolic parameters to evaluate markers of inflammation, body mass variation, and glucose tolerance in mice fed a high-fat diet.ResultsUsing a real-time PCR array, we identified leukemia inhibitory factor as a chemokine/cytokine undergoing a rapid increase in the hypothalamus of obesity-resistant and a rapid decrease in the hypothalamus of obesity-prone mice fed a high-fat diet for 1 day. We hypothesized that the increased hypothalamic expression of leukemia inhibitory factor could contribute to the protective phenotype of obesity-resistant mice. To test this hypothesis, we immunoneutralized hypothalamic leukemia inhibitory factor and evaluated inflammatory and metabolic parameters. The immunoneutralization of leukemia inhibitory factor in the hypothalamus of obesity-resistant mice resulted in increased body mass gain and increased adiposity. Body mass gain was mostly due to increased caloric intake and reduced spontaneous physical activity. This modification in the phenotype was accompanied by increased expression of inflammatory cytokines in the hypothalamus. In addition, the inhibition of hypothalamic leukemia inhibitory factor was accompanied by glucose intolerance and insulin resistance.ConclusionHypothalamic expression of leukemia inhibitory factor may protect mice from the development of diet-induced obesity; the inhibition of this protein in the hypothalamus transforms obesity-resistant into obesity-prone mice.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0956-9) contains supplementary material, which is available to authorized users.

show abstract

“…Consistent with this notion, Pomc-null mice are obese 27 . Interestingly, in mice fed a high-fat diet, reduced hypothalamic Pomc expression was found to be the earliest marker predicting obesity 28 . The ability of MetAP2 inhibition to be effective in various models may indicate that MetAP2 acts on a common pathway that is misregulated in all models leading to increased appetite and obesity.…”

Section: Discussionmentioning

confidence: 99%

MetAP2 inhibition reduces food intake and body weight in a ciliopathy mouse model of obesity

Pottorf

Fagan

Burkey

et al. 2019

Preprint

View full text Add to dashboard Cite

The ciliopathies Bardet-Biedl Syndrome and Alström Syndrome are genetically inherited pleiotropic disorders with primary clinical features of hyperphagia and obesity. Methionine aminopeptidase 2 inhibitors (MetAP2i) have been shown in preclinical and clinical studies to reduce food intake, body weight, and adiposity. Here we investigated the effects of MetAP2i administration in a mouse model of ciliopathy produced by conditional deletion of the Thm1 gene in adulthood (Thm1 cko). Thm1 cko mice show decreased hypothalamic proopiomelanocortin expression as well as hyperphagia, obesity, metabolic disease and hepatic steatosis. In obese Thm1 cko mice, two-week administration of MetAP2i reduced daily food intake and reduced body weight 17.1% from baseline (vs. 5% reduction for vehicle). This was accompanied with decreased levels of blood glucose, insulin and leptin. Further, MetAP2i reduced gonadal adipose depots and adipocyte size and improved liver morphology. This is the first report of MetAP2i reducing hyperphagia and body weight, and ameliorating metabolic indices in a mouse model of ciliopathy. These results support further investigation of MetAP2 inhibition as a potential therapeutic strategy for ciliary-mediated forms of obesity.

show abstract

Defective regulation of POMC precedes hypothalamic inflammation in diet-induced obesity

Cited by 56 publications

References 42 publications

Quercetin Protects Obesity-Induced Hypothalamic Inflammation by Reducing Microglia-Mediated Inflammatory Responses via HO-1 Induction

Quercetin Protects Obesity-Induced Hypothalamic Inflammation by Reducing Microglia-Mediated Inflammatory Responses via HO-1 Induction

Inhibition of hypothalamic leukemia inhibitory factor exacerbates diet-induced obesity phenotype

MetAP2 inhibition reduces food intake and body weight in a ciliopathy mouse model of obesity

Contact Info

Product

Resources

About