Ginger and avocado as nutraceuticals for obesity and its comorbidities.

Obesity is a worldwide epidemic and is one of the factors involved in the etiology of type 2 diabetes mellitus. Obesity induces low-grade inflammation and oxidative stress. The treatment for obesity involves changes in diet, physical activity, and even medication and surgery. Currently, the use of nutraceutical compounds is associated with health benefits. Ginger and avocado are used for many people all around the world; however, its effect as a nutraceutical compound is less known by the general population. For this reason, we searched information of the literature to point its effects on distinct mechanisms of defense against the obesity its comorbidities. The present review aimed showing that these nutraceuticals may be useful in obesity treatment. Reports have shown that ginger and avocado induce antioxidant and anti-inflammatory effects by improving enzymatic activity and modulating obesity-related impairments in the anti-inflammatory system in different tissues, without side effects. Furthermore, ginger and avocado were found to be effective in reversing the harmful effects of obesity on blood lipids. In conclusion, on the basis of the positive effects of ginger and avocado in in vitro, animal, and human studies, these nutraceuticals may be useful in obesity treatment.

Lithium and valproate act on the GSK-3ß signaling pathway to reverse manic-like behavior in an animal model of mania induced by ouabain.

The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on the PI3K/Akt signaling pathway in the brains of rats subjected to the ouabain (OUA)-induced animal model of mania. In addition, the effects of AR-A014418, a GSK-3ß inhibitor, on manic-like behavior induced by OUA were evaluated. In the first experimental protocol Wistar rats received a single ICV injection of OUA or artificial cerebrospinal fluid (aCSF). From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li or VPA twice a day. In the second experimental protocol, rats received OUA, aCSF, OUA plus AR-A014418, or aCSF plus AR-A014418. On the 7th day after OUA injection, locomotor activity was measured using the open-field test. In addition, we analyzed the levels of p-PI3K, p-MAPK, p-Akt, and p-GSK-3ß in the brain of rats by immunoblot. Li and VPA reversed OUA-related hyperactivity. OUA decreased p-PI3K, p-Akt and p-GSK-3ß levels. Li and VPA improved these OUA-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. In addition, AR-A014418 reversed the manic-like behavior induced by OUA. These findings suggest that the manic-like effects of ouabain are associated with the activation of GSK-3ß, and that Li and VPA exert protective effects against OUA-induced inhibition of the GSK-3ß pathway.

Effect of Low-Power Laser (LPL) and Light-Emitting Diode (LED) on Inflammatory Response in Burn Wound Healing.

The aim of the study was to investigate the biochemical and molecular changes in the process of epidermal healing of burn injuries after therapeutic treatment with low-power laser (LPL) and light-emitting diode (LED). Rats were divided into six groups: skin without injury (Sham), burn wounds (BWs), BW + 660-nm LPL, BW + 904-nm LPL, BW + 632-nm LED, and BW + 850-nm LED. The burn wound model was performed using a 100 °C copper plate, with 10 s of contact in the skin. The irradiations started 24 h after the lesion and were performed daily for 7 days. The burn wound groups showed an increase in the superoxide production, dichlorofluorescein, nitrites, and high protein oxidative damage. The activities of glutathione peroxidase and catalase were also increased, and a significant reduction in glutathione levels was observed compared to the control group. However, treatments with 660-nm LPL and 850-nm LED promoted protection against to oxidative stress, and similar results were also observed in the IL-6 and pERK1/2 expression. Taken together, these results suggest that LPL 660 nm and LED 850 nm appear reduced in the inflammatory response and oxidative stress parameters, thus decreasing dermal necrosis and increasing granulation tissue formation, in fact accelerating the repair of burn wounds.

Hypothalamic S1P/S1PR1 axis controls energy homeostasis.

Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-protein-coupled receptor for sphingosine-1-phosphate (S1P) that has a role in many physiological and pathophysiological processes. Here we show that the S1P/S1PR1 signalling pathway in hypothalamic neurons regulates energy homeostasis in rodents. We demonstrate that S1PR1 protein is highly enriched in hypothalamic POMC neurons of rats. Intracerebroventricular injections of the bioactive lipid, S1P, reduce food consumption and increase rat energy expenditure through persistent activation of STAT3 and the melanocortin system. Similarly, the selective disruption of hypothalamic S1PR1 increases food intake and reduces the respiratory exchange ratio. We further show that STAT3 controls S1PR1 expression in neurons via a positive feedback mechanism. Interestingly, several models of obesity and cancer anorexia display an imbalance of hypothalamic S1P/S1PR1/STAT3 axis, whereas pharmacological intervention ameliorates these phenotypes. Taken together, our data demonstrate that the neuronal S1P/S1PR1/STAT3 signalling axis plays a critical role in the control of energy homeostasis in rats.

Effects of taurine supplementation following eccentric exercise in young adults.

The purpose of the present study was to investigate the effects of taurine supplementation on muscle performance, oxidative stress, and inflammation response after eccentric exercise (EE) in males. Twenty-one participants (mean age, 21 ± 6 years; weight, 78.2 ± 5 kg; height, 176 ± 7 cm) were selected and randomly divided into two groups: placebo (n = 10) and taurine (n = 11). Fourteen days after starting supplementation, subjects performed EE (3 sets until exhaustion, with EE of the elbow flexors on the Scott bench, 80% 1 repetition maximum (RM)). Blood samples were collected and muscle performance was measured on days 1, 14, 16, 18, and 21 after starting the supplements. Then, performance, muscle damage, oxidative stress, and inflammatory markers were analyzed. The taurine supplementation resulted in increased strength levels and thiol total content and decreased muscle soreness, lactate dehydrogenase level, creatine kinase activity, and oxidative damage (xylenol and protein carbonyl). Antioxidant enzymes (superoxide dismutase, catalase, and gluthatione peroxidase) and inflammatory markers (tumor necrosis factor, interleukin-1ß (IL-1ß), and interleukin-10 (IL-10)) were not altered during the recovery period compared with the placebo group. The results suggest that taurine supplementation represents an important factor in improving performance and decreasing muscle damage and oxidative stress but does not decrease the inflammatory response after EE.

Acute exercise suppresses hypothalamic PTP1B protein level and improves insulin and leptin signaling in obese rats.

Hypothalamic inflammation is associated with insulin and leptin resistance, hyperphagia, and obesity. In this scenario, hypothalamic protein tyrosine phosphatase 1B (PTP1B) has emerged as the key phosphatase induced by inflammation that is responsible for the central insulin and leptin resistance. Here, we demonstrated that acute exercise reduced inflammation and PTP1B protein level/activity in the hypothalamus of obese rodents. Exercise disrupted the interaction between PTP1B with proteins involved in the early steps of insulin (IRß and IRS-1) and leptin (JAK2) signaling, increased the tyrosine phosphorylation of these molecules, and restored the anorexigenic effects of insulin and leptin in obese rats. Interestingly, the anti-inflammatory action and the reduction of PTP1B activity mediated by exercise occurred in an interleukin-6 (IL-6)-dependent manner because exercise failed to reduce inflammation and PTP1B protein level after the disruption of hypothalamic-specific IL-6 action in obese rats. Conversely, intracerebroventricular administration of recombinant IL-6 reproduced the effects of exercise, improving hypothalamic insulin and leptin action by reducing the inflammatory signaling and PTP1B activity in obese rats at rest. Taken together, our study reports that physical exercise restores insulin and leptin signaling, at least in part, by reducing hypothalamic PTP1B protein level through the central anti-inflammatory response.

Resveratrol and fish oil reduce catecholamine-induced mortality in obese rats: role of oxidative stress in the myocardium and aorta.

The exact mechanisms of the relationship between obesity and cardiovascular events are not yet fully understood; however, oxidative stress may be involved. Thus, the aim of the present study was to evaluate the effects of resveratrol and fish oil on catecholamine-induced mortality in obese rats. To begin with, rats were divided into five groups: (1) lean, (2) obese, (3) obese supplemented with resveratrol, (4) obese supplemented with fish oil and (5) obese supplemented with resveratrol and fish oil (n 18 rats per group), for 2 months. After supplementation, the groups were subdivided as with (n 10) and without (n 8) cardiovascular catecholaminergic stress after isoproterenol (60 mg/kg) injection. At 24 h later, the survival rate was analysed. The obese group showed lower survival rates (10 %) when compared with the lean group (70 %). On the other hand, resveratrol (50 %) and fish oil (40 %) increased the survival rate of obese rats (χ(2) test, P= 0·019). Biochemical analyses of the myocardium and aorta revealed that obese rats had higher levels of superoxide and oxidative damage to lipids and protein. This was associated with reduced superoxide dismutase and glutathione peroxidase activity in both the myocardium and aorta. The supplementation increased antioxidant enzyme activities and reduced oxidative damage. We also evaluated the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 antioxidant pathway. Nrf2 protein levels that were reduced in obese rats were increased by the antioxidant treatment. Taken together, these results showed that resveratrol and fish oil reduce catecholamine-induced mortality in obese rats, partly through the reduction of oxidative stress.

Creatine supplementation does not decrease oxidative stress and inflammation in skeletal muscle after eccentric exercise.

Thirty-six male rats were used; divided into 6 groups (n = 6): saline; creatine (Cr); eccentric exercise (EE) plus saline 24 h (saline + 24 h); eccentric exercise plus Cr 24 h (Cr + 24 h); eccentric exercise plus saline 48 h (saline + 48 h); and eccentric exercise plus Cr 48 h (Cr + 48 h). Cr supplementation was administered as a solution of 300 mg · kg body weight(-1) · day(-1) in 1 mL water, for two weeks, before the eccentric exercise. The animals were submitted to one downhill run session at 1.0 km · h(-1) until exhaustion. Twenty-four and forty-eight hours after the exercise, the animals were killed, and the quadriceps were removed. Creatine kinase levels, superoxide production, thiobarbituric acid reactive substances (TBARS) level, carbonyl content, total thiol content, superoxide dismutase, catalase, glutathione peroxidase, interleukin-1b (IL-1ß), nuclear factor kappa B (NF-kb), and tumour necrosis factor (TNF) were analysed. Cr supplementation neither decreases Cr kinase, superoxide production, lipoperoxidation, carbonylation, total thiol, IL-1ß, NF-kb, or TNF nor alters the enzyme activity of superoxide dismutase, catalase, and glutathione peroxides in relation to the saline group, respectively (P < 0.05). There are positive correlations between Cr kinase and TBARS and TNF-α 48 hours after eccentric exercise. The present study suggests that Cr supplementation does not decrease oxidative stress and inflammation after eccentric contraction.

Green tea extract supplementation induces the lipolytic pathway, attenuates obesity, and reduces low-grade inflammation in mice fed a high-fat diet.

The aim of this study was to evaluate the effects of green tea Camellia sinensis extract on proinflammatory molecules and lipolytic protein levels in adipose tissue of diet-induced obese mice. Animals were randomized into four groups: CW (chow diet and water); CG (chow diet and water + green tea extract); HW (high-fat diet and water); HG (high-fat diet and water + green tea extract). The mice were fed ad libitum with chow or high-fat diet and concomitantly supplemented (oral gavage) with 400 mg/kg body weight/day of green tea extract (CG and HG, resp.). The treatments were performed for eight weeks. UPLC showed that in 10 mg/mL green tea extract, there were 15 µg/mg epigallocatechin, 95 µg/mg epigallocatechin gallate, 20.8 µg/mg epicatechin gallate, and 4.9 µg/mg gallocatechin gallate. Green tea administered concomitantly with a high-fat diet increased HSL, ABHD5, and perilipin in mesenteric adipose tissue, and this was associated with reduced body weight and adipose tissue gain. Further, we observed that green tea supplementation reduced inflammatory cytokine TNFα levels, as well as TLR4, MYD88, and TRAF6 proinflammatory signalling. Our results show that green tea increases the lipolytic pathway and reduces adipose tissue, and this may explain the attenuation of low-grade inflammation in obese mice.

Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity.

BACKGROUND: In experimental models, hypothalamic inflammation is an early and determining factor in the installation and progression of obesity. Pharmacological and gene-based approaches have proven efficient in restraining inflammation and correcting the obese phenotypes. However, the role of nutrients in the modulation of hypothalamic inflammation is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that, in a mouse model of diet-induced obesity, partial substitution of the fatty acid component of the diet by flax seed oil (rich in C18:3) or olive oil (rich in C18:1) corrects hypothalamic inflammation, hypothalamic and whole body insulin resistance, and body adiposity. In addition, upon icv injection in obese rats, both ω3 and ω9 pure fatty acids reduce spontaneous food intake and body mass gain. These effects are accompanied by the reversal of functional and molecular hypothalamic resistance to leptin/insulin and increased POMC and CART expressions. In addition, both, ω3 and ω9 fatty acids inhibit the AMPK/ACC pathway and increase CPT1 and SCD1 expression in the hypothalamus. Finally, acute hypothalamic injection of ω3 and ω9 fatty acids activate signal transduction through the recently identified GPR120 unsaturated fatty acid receptor. CONCLUSIONS/SIGNIFICANCE: Unsaturated fatty acids can act either as nutrients or directly in the hypothalamus, reverting diet-induced inflammation and reducing body adiposity. These data show that, in addition to pharmacological and genetic approaches, nutrients can also be attractive candidates for controlling hypothalamic inflammation in obesity.

Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain.

A growing body of evidence has pointed to the N-methyl-d-aspartate (NMDA) receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study investigated the possibility of synergistic interactions between antidepressant imipramine with the uncompetitive NMDA receptor antagonist ketamine. Wistar rats were acutely treated with ketamine (5 and 10mg/kg) and imipramine (10 and 20mg/kg) and then subjected to forced swimming tests. The cAMP response element bindig (CREB) and brain-derived neurotrophic factor (BDNF) protein levels and protein kinase C (PKC) and protein kinase A (PKA) phosphorylation were assessed in the prefrontal cortex, hippocampus and amygdala by imunoblot. Imipramine at the dose of 10mg/kg and ketamine at the dose of 5mg/kg did not have effect on the immobility time; however, the effect of imipramine (10 and 20mg/kg) was enhanced by both doses of ketamine. Ketamine and imipramine alone or in combination at all doses tested did not modify locomotor activity. Combined treatment with ketamine and imipramine produced stronger increases of CREB and BDNF protein levels in the prefrontal cortex, hippocampus and amygdala, and PKA phosphorylation in the hippocampus and amygdala and PKC phosphorylation in prefrontal cortex. The results described indicate that co-administration of antidepressant imipramine with ketamine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone. This finding may be of particular importance in the case of drug-resistant patients and could suggest a method of obtaining significant antidepressant actions whilst limiting side effects.

Taurine supplementation decreases oxidative stress in skeletal muscle after eccentric exercise.

Infrequent exercise, typically involving eccentric actions, has been shown to cause oxidative stress and to damage muscle tissue. High taurine levels are present in skeletal muscle and may play a role in cellular defences against free radical-mediated damage. This study investigates the effects of taurine supplementation on oxidative stress biomarkers after eccentric exercise (EE). Twenty-four male rats were divided into the following groups (n = 6): control; EE; EE plus taurine (EE + Taurine); EE plus saline (EE + Saline). Taurine was administered as a 1-ml 300 mg kg(-1) per body weight (BW) day(-1) solution in water by gavage, for 15 consecutive days. Starting on the 14th day of supplementation, the animals were submitted to one 90-min downhill run session and constant velocity of 1·0 km h(-1) . Forty-eight hours after the exercise session, the animals were killed and the quadriceps muscles were surgically removed. Production of superoxide anion, creatine kinase (CK) levels, lipoperoxidation, carbonylation, total thiol content and antioxidant enzyme were analysed. Taurine supplementation was found to decrease superoxide radical production, CK, lipoperoxidation and carbonylation levels and increased total thiol content in skeletal muscle, but it did not affect antioxidant enzyme activity after EE. The present study suggests that taurine affects skeletal muscle contraction by decreasing oxidative stress, in association with decreased superoxide radical production.

IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKbeta and ER stress inhibition.

Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKbeta activation and endoplasmic reticulum (ER) stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKbeta/NF-kappaB activation by a mechanism dependent upon the pro-inflammatory cytokine interleukin (IL)-6. The disruption of hypothalamic-specific IL-6 action blocked the beneficial effects of exercise on the re-balance of food intake and insulin and leptin resistance. This molecular mechanism, mediated by physical activity, involves the anti-inflammatory protein IL-10, a core inhibitor of IKKbeta/NF-kappaB signaling and ER stress. We report that exercise and recombinant IL-6 requires IL-10 expression to suppress hyperphagia-related obesity. Moreover, in contrast to control mice, exercise failed to reverse the pharmacological activation of IKKbeta and ER stress in C3H/HeJ mice deficient in hypothalamic IL-6 and IL-10 signaling. Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin.

Vitamin E supplementation decreases muscular and oxidative damage but not inflammatory response induced by eccentric contraction.

The purpose of this study was to investigate the effects of vitamin E supplementation on muscular and oxidative damage, as well as the inflammatory response induced by eccentric exercise (EE) in humans. Twenty-one participants with a mean age of 22.5 +/- 4 years, weight of 68.2 +/- 4.9 kg, and height of 173 +/- 4.3 cm were selected and divided randomly into two groups: supplemented (S) (n = 11) and placebo (P) (n = 10). Fourteen days after starting supplementation, subjects performed EE (three sets until exhaustion with elbow flexion and extension on the Scott bench, 80% 1 RM). Blood samples were collected on days 0, 2, 4, and 7 after EE. Muscle soreness (MS), lactate dehydrogenase (LDH) activity, lipid peroxidation, protein carbonylation, tumor necrosis factor-alpha (TNF-alpha), and interleukin 10 (IL-10) levels were determined. We measured a significant increase in MS, LDH, lipid peroxidation, and carbonylation in both groups on days 2, 4, and 7 after eccentric contractions (EC). Values of the supplement group were lower than those of the placebo group at 4 and 7 days after EC in all parameters. Both groups showed significantly increased TNF-alpha on the second day and IL-10 concentration on the fourth and seventh days after EE. The results suggest that vitamin E supplementation represents an important factor in the defense against oxidative stress and muscle damage but not against the inflammatory response in humans.

Inhibition of hypothalamic Foxo1 expression reduced food intake in diet-induced obesity rats.

Insulin signalling in the hypothalamus plays a role in maintaining body weight. The forkhead transcription factor Foxo1 is an important mediator of insulin signalling in the hypothalamus. Foxo1 stimulates the transcription of the orexigenic neuropeptide Y and Agouti-related protein through the phosphatidylinositol-3-kinase/Akt signalling pathway, but the role of hypothalamic Foxo1 in insulin resistance and obesity remains unclear. Here, we identify that a high-fat diet impaired insulin-induced hypothalamic Foxo1 phosphorylation and degradation, increasing the nuclear Foxo1 activity and hyperphagic response in rats. Thus, we investigated the effects of the intracerebroventricular (i.c.v.) microinfusion of Foxo1-antisense oligonucleotide (Foxo1-ASO) and evaluated the food consumption and weight gain in normal and diet-induced obese (DIO) rats. Three days of Foxo1-ASO microinfusion reduced the hypothalamic Foxo1 expression by about 85%. i.c.v. infusion of Foxo1-ASO reduced the cumulative food intake (21%), body weight change (28%), epididymal fat pad weight (22%) and fasting serum insulin levels (19%) and increased the insulin sensitivity (34%) in DIO but not in control animals. Collectively, these data showed that the Foxo1-ASO treatment blocked the orexigenic effects of Foxo1 and prevented the hyperphagic response in obese rats. Thus, pharmacological manipulation of Foxo1 may be used to prevent or treat obesity.

Diet-induced inflammation of the hypothalamus in obesity.

Dysfunction of specific hypothalamic neurons is regarded as an important mechanism predisposing to the development of obesity. Recent studies have revealed that the consumption of fat-rich foods can activate an inflammatory response in the hypothalamus, which disturbs the anorexigenic and thermogenic signals generated by the hormones leptin and insulin, leading in turn to anomalous body mass control. Depending on diet composition, cytokines are expressed in the hypothalamus, contributing to the activation of intracellular inflammatory signal transduction. At least 4 distinct signaling pathways have been identified and the molecular mechanisms leading to the impairment of the leptin and insulin actions have been determined. Here, we present the mechanisms involved in diet-induced resistance to leptin and insulin action in the hypothalamus and discuss some of the potential applications of this knowledge in the therapeutics of obesity.

Distinct subsets of hypothalamic genes are modulated by two different thermogenesis-inducing stimuli.

Obesity results from an imbalance between food intake and energy expenditure, two vital functions that are tightly controlled by specialized neurons of the hypothalamus. The complex mechanisms that integrate these two functions are only beginning to be deciphered. The objective of this study was to determine the effect of two thermogenesis-inducing conditions, i.e., ingestion of a high-fat (HF) diet and exposure to cold environment, on the expression of 1,176 genes in the hypothalamus of Wistar rats. Hypothalamic gene expression was evaluated using a cDNA macroarray approach. mRNA and protein expressions were determined by reverse-transcription PCR (RT-PCR) and immunoblot. Cold exposure led to an increased expression of 43 genes and to a reduced expression of four genes. HF diet promoted an increased expression of 90 genes and a reduced expression of 78 genes. Only two genes (N-methyl-D-aspartate (NMDA) receptor 2B and guanosine triphosphate (GTP)-binding protein G-alpha-i1) were similarly affected by both thermogenesis-inducing conditions, undergoing an increment of expression. RT-PCR and immunoblot evaluations confirmed the modulation of NMDA receptor 2B and GTP-binding protein G-alpha-i1, only. This corresponds to 0.93% of all the responsive genes and 0.17% of the analyzed genes. These results indicate that distinct environmental thermogenic stimuli can modulate predominantly distinct profiles of genes reinforcing the complexity and multiplicity of the hypothalamic mechanisms that regulate energy conservation and expenditure.

Infliximab restores glucose homeostasis in an animal model of diet-induced obesity and diabetes.

TNF-alpha plays an important role in obesity-linked insulin resistance and diabetes mellitus by activating at least two serine kinases capable of promoting negative regulation of key elements of the insulin signaling pathway. Pharmacological inhibition of TNF-alpha is currently in use for the treatment of rheumatoid and psoriatic arthritis, and some case reports have shown clinical improvement of diabetes in patients treated with the TNF-alpha blocking monoclonal antibody infliximab. The objective of this study was to evaluate the effect of infliximab on glucose homeostasis and insulin signal transduction in an animal model of diabetes. Diabetes was induced in Swiss mice by a fat-rich diet. Glucose and insulin homeostasis were evaluated by glucose and insulin tolerance tests and by the hyperinsulinemic-euglycemic clamp. Signal transduction was evaluated by immunoprecipitation and immunoblotting assays. Short-term treatment with infliximab rapidly reduced blood glucose and insulin levels and glucose and insulin areas under the curve during a glucose tolerance test. Furthermore, infliximab increased the glucose decay constant during an insulin tolerance test and promoted a significant increase in glucose infusion rate during a hyperinsulinemic-euglycemic clamp. In addition, the clinical outcomes were accompanied by improved insulin signal transduction in muscle, liver, and hypothalamus, as determined by the evaluation of insulin-induced insulin receptor, insulin receptor substrate-1, and receptor substrate-2 tyrosine phosphorylation and Akt and forkhead box protein O1 serine phosphorylation. Thus, pharmacological inhibition of TNF-alpha may be an attractive approach to treat severely insulin-resistant patients with type 2 diabetes mellitus.

A central role for neuronal adenosine 5'-monophosphate-activated protein kinase in cancer-induced anorexia.

The pathogenesis of cancer anorexia is multifactorial and associated with disturbances of the central physiological mechanisms controlling food intake. However, the neurochemical mechanisms responsible for cancer-induced anorexia are unclear. Here we show that chronic infusion of 5-amino-4imidazolecarboxamide-riboside into the third cerebral ventricle and a chronic peripheral injection of 2 deoxy-d-glucose promotes hypothalamic AMP-activated protein kinase (AMPK) activation, increases food intake, and prolongs the survival of anorexic tumor-bearing (TB) rats. In parallel, the pharmacological activation of hypothalamic AMPK in TB animals markedly reduced the hypothalamic production of inducible nitric oxide synthase, IL-1beta, and TNF-alpha and modulated the expression of proopiomelanocortin, a hypothalamic neuropeptide that is involved in the control of energy homeostasis. Furthermore, the daily oral and intracerebroventricular treatment with biguanide antidiabetic drug metformin also induced AMPK phosphorylation in the central nervous system and increased food intake and life span in anorexic TB rats. Collectively, the findings of this study suggest that hypothalamic AMPK activation reverses cancer anorexia by inhibiting the production of proinflammatory molecules and controlling the neuropeptide expression in the hypothalamus, reflecting in a prolonged life span in TB rats. Thus, our data indicate that hypothalamic AMPK activation presents an attractive opportunity for the treatment of cancer-induced anorexia.

Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus.

Obesity has reached epidemic proportions in several regions of the world. General changes in lifestyle, including consumption of fat-rich food, are among the most important factors leading to an unprecedented increase in the prevalence of this disease. Weight gain results from an imbalance between caloric intake and energy expenditure. Both of these parameters are under the tight control of specialized neurons of the hypothalamus that respond to peripheral anorexigenic and adipostatic signals carried by leptin and insulin. Here we show, by macroarray analysis, that high-fat feeding [hyperlipidic diet (HL)] induces the expression of several proinflammatory cytokines and inflammatory responsive proteins in hypothalamus. This phenomenon is accompanied by increased activation of c-Jun N-terminal kinase and nuclear factor-kappaB. In addition, HL feeding leads to impaired functional and molecular activation of the insulin-signaling pathway, which is paralleled by increased serine phosphorylation of the insulin receptor and insulin receptor substrate-2. Intracerebroventricular treatment of HL rats with a specific inhibitor of c-Jun N-terminal kinase (SP600125) restores insulin signaling and leads to a reduced caloric intake and weight loss. We conclude that HL feeding induces a local proinflammatory status in the hypothalamus, which results in impaired anorexigenic insulin signaling.