Tumor necrosis factor‐α activates signal transduction in hypothalamus and modulates the expression of pro‐inflammatory proteins and orexigenic/anorexigenic neurotransmitters

Amaral, Maria Esméria Corezola do; Barbuio, Raquel; Milanski, Marciane; Romanatto, Talita; Barbosa, Helena C.; Nadruz, Wilson; Bértolo, Manoel Barros; Boschero, Antônio Carlos; Saad, Mário J.A.; Franchini, Kleber G.; Velloso, Lı́cio A.

doi:10.1111/j.1471-4159.2006.03857.x

Cited by 58 publications

(51 citation statements)

References 55 publications

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“…mRNA isolation and RT-PCR. mRNA isolation and RT-PCR were performed as previously described (30). The primers used were as follows: RPS-29 (NCBI: NM012876), sense: 5Ј-AGGCAAGATGGGTCACCAGC-3Ј, antisense: 5Ј-AGTCGAATCATCCATTCAGGTCG-3Ј; neuropeptide Y (NPY) (NCBI: NM012614), sense: 5Ј-AGAGATC CAGCCCT GAGACA-3Ј, antisense: 5Ј-AACG ACAACAAGGGAAATGG-3Ј; pro-opiomelanocortin (POMC) (NCBI: AF510391), sense: 5Ј-CTCCTGCTTCAGACCTCCAT-3Ј, antisense: 5Ј-TTGGGG TACACCTTCACAGG-3Ј.…”

Section: Methodsmentioning

confidence: 99%

A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss

et al. 2008

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OBJECTIVE-A high-protein diet (HPD) is known to promote the reduction of body fat, but the mechanisms underlying this change are unclear. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) function as majors regulators of cellular metabolism that respond to changes in energy status, and recent data demonstrated that they also play a critical role in systemic energy balance. Here, we sought to determine whether the response of the AMPK and mTOR pathways could contribute to the molecular effects of an HPD.RESEARCH DESIGN AND METHODS-Western blotting, confocal microscopy, chromatography, light microscopy, and RT-PCR assays were combined to explore the anorexigenic effects of an HPD.RESULTS-An HPD reduced food intake and induced weight loss in both normal rats and ob/ob mice. The intracerebroventricular administration of leucine reduced food intake, and the magnitude of weight loss and reduction of food intake in a leucine-supplemented diet are similar to that achieved by HPD in normal rats and in ob/ob mice, suggesting that leucine is a major component of the effects of an HPD. Leucine and HPD decrease AMPK and increase mTOR activity in the hypothalamus, leading to inhibition of neuropeptide Y and stimulation of pro-opiomelanocortin expression. Consistent with a cross-regulation between AMPK and mTOR to control food intake, our data show that the activation of these enzymes occurs in the same specific neuronal subtypes.CONCLUSIONS-These findings provide support for the hypothesis that AMPK and mTOR interact in the hypothalamus to regulate feeding during HPD in a leucine-dependent manner.

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Section: Methodsmentioning

confidence: 99%

A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss

et al. 2008

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“…TNF␣-injected icv induces hypothalamic resistance to leptin and insulin (30) and modulates neurotransmitter expression toward an obesity-like phenotype (28,31). icv TNF␣ produced no change in the peripheral levels of this cytokine; nevertheless, insulin in blood increased significantly, whereas a loss of the first phase secretion was observed during an ipGTT.…”

Section: Discussionmentioning

confidence: 96%

Inflammation of the Hypothalamus Leads to Defective Pancreatic Islet Function

Calegari

Torsoni

Vanzela

et al. 2011

Journal of Biological Chemistry

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Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic ␤-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic ␤-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor ␣ leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal-induced peroxisome proliferator receptor-␥ coactivator ⌬␣ and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1␣ expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion.

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“…40 In fact, intracerebroventricular injection of TNF-a reportedly increased the NPY mRNA level in the hypothalamus but reduced food intake, 41 and proinflammatory signals decreased the secretion of AgRP but increased the transcription of the AgRP gene. 42 On the other hand, the rats treated with 1a,25(OH) 2 D 3 had reduced body weight without changes in feeding-regulating peptide gene expression.…”

Section: Discussionmentioning

confidence: 99%

Similar changes of hypothalamic feeding‐regulating peptides mRNAs and plasma leptin levels in PTHrP‐, LIF‐secreting tumors‐induced cachectic rats and adjuvant arthritic rats

Suzuki

Hashimoto

Kawasaki

et al. 2011

Intl Journal of Cancer

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Parathyroid hormone-related protein (PTHrP) is a causative factor of humoral hypercalcemia in malignancy. However, it is difficult to explain the mechanism of anorexia/cachexia with PTHrP secretion in detail. Previously, we demonstrated that the expressions of orexigenic peptides increased and anorexigenic peptides decreased under cachectic conditions in rats carrying tumors secreting PTHrP. In this study, we investigated whether such changes in the expression of hypothalamic feedingregulating peptides can be solely attributed to PTHrP or are a general response under cachectic conditions. Cachectic syndromes were induced in rats by: (i) inoculation of human lung cancer LC-6 cells that secreted PTHrP, (ii) inoculation of human melanoma SEKI cells that secrete not PTHrP but LIF1, (iii) injection of heat-killed Mycobacterium leading to arthritis (AA) and (iv) oral administration of a high dose of 1a,25(OH) 2 D 3 that resulted in hypercalcemia. The LC-6-bearing rats and AA rats were treated with or without anti-PTHrP antibody and indomethacin, respectively, and the expression of the hypothalamic feeding-regulating peptide mRNAs were examined by in situ hybridization histochemistry. The orexigenic peptide mRNAs, such as neuropeptide Y and agouti-related protein, were significantly increased, and that of anorexigenic peptide mRNAs, such as proopiomelanocortin, cocaine-and amphetamine-regulated transcript and corticotropin-releasing hormone were significantly decreased when they developed cachectic syndromes and AA. A high dose of 1a,25(OH) 2 D 3 caused hypercalcemia and body weight loss but did not affect the expression of hypothalamic feeding-regulating peptide mRNAs. The expressions of the hypothalamic feedingregulating peptides change commonly in different chronic cachectic models without relating to serum calcium levels.Cachexia is characterized by weight loss involving massive depletion of adipose tissue and lean body mass. Nutritional supplementation cannot replenish the loss of lean body mass. 1,2The severity of cachexia in disease states such as cancer, endstage renal disease, rheumatoid arthritis (RA) and acquired immunodeficiency syndrome may be the primary determining factor in both the quality of life and eventual mortality.3,4 Hypercalcemia is also a frequent paraneoplastic syndrome and represents an important factor affecting the morbidity and mortality of cancer patients. 5 The main cause of humoral hypercalcemia in malignancy (HHM) is the tumor production of parathyroid hormone-related protein (PTHrP) that stimulates osteoclastic resorption and renal reabsorption of calcium. The homeostasis of food intake and body weight is controlled by complex mechanisms. The hypothalamus receives and integrates the neural and humoral signals that inform energy status from peripheral tissues.7 Appetite and feeding behaviors are primarily controlled by feeding centers in the lateral hypothalamic area (LHA), the satiety center in the ventromedial hypothalamic nucleus, the arcuate nucleus (Arc) and the paraventricular n...

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Tumor necrosis factor‐α activates signal transduction in hypothalamus and modulates the expression of pro‐inflammatory proteins and orexigenic/anorexigenic neurotransmitters

Cited by 58 publications

References 55 publications

A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss

A Central Role for Neuronal AMP-Activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in High-Protein Diet–Induced Weight Loss

Inflammation of the Hypothalamus Leads to Defective Pancreatic Islet Function

Similar changes of hypothalamic feeding‐regulating peptides mRNAs and plasma leptin levels in PTHrP‐, LIF‐secreting tumors‐induced cachectic rats and adjuvant arthritic rats

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