TNF-α acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient—Effects on leptin and insulin signaling pathways

Romanatto, Talita; Cesquini, Maristela; Amaral, Maria Esméria Corezola do; Roman, Erika; Moraes, João Carlos Silos; Torsoni, Márcio Alberto; Cruz‐Neto, Ariovaldo P.; Velloso, Lı́cio A.

doi:10.1016/j.peptides.2007.03.006

Cited by 118 publications

(105 citation statements)

References 35 publications

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“…This is evidenced by reduced relative thermogenesis in obesity (32) and by reduced thermogenesis in animals treated with a low dose of exogenous TNF-␣ (33). These dose-dependent effects of TNF-␣ on thermogenesis may depend at least in part on its hypothalamic actions that control the local activity of leptin and insulin (12).…”

Section: Discussionmentioning

confidence: 99%

“…Intracerebroventricular Cannulation-Rats were stereotaxically instrumented using a Stoelting stereotaxic apparatus, according to a method previously described (12). A cannula was placed in the lateral ventricule and efficiency was tested 1 week after cannulation by the evaluation of the drinking response elicited by angiotensin II-injected intracerebroventricularly (13).…”

Section: Experimental Model and Feeding Protocols-male Tnfrp55mentioning

confidence: 99%

“…Insulin Tolerance Test-Insulin (0.5 units/kg body mass) was administered by intraperitoneal injection, and blood samples were collected at 0, 4,8,12,16, and 20 min for serum glucose determination. The constant for glucose disappearance rate during the test (Kitt) was calculated using the formula 0.693/t1 ⁄ 2 .…”

Section: Experimental Model and Feeding Protocols-male Tnfrp55mentioning

confidence: 99%

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Deletion of Tumor Necrosis Factor-α Receptor 1 (TNFR1) Protects against Diet-induced Obesity by Means of Increased Thermogenesis

Romanatto

Roman

Arruda

et al. 2009

Journal of Biological Chemistry

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129

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In diet-induced obesity, hypothalamic and systemic inflammatory factors trigger intracellular mechanisms that lead to resistance to the main adipostatic hormones, leptin and insulin. Tumor necrosis factor-␣ (TNF-␣) is one of the main inflammatory factors produced during this process and its mechanistic role as an inducer of leptin and insulin resistance has been widely investigated. Most of TNF-␣ inflammatory signals are delivered by TNF receptor 1 (R1); however, the role played by this receptor in the context of obesity-associated inflammation is not completely known. Here, we show that TNFR1 knock-out (TNFR1 KO) mice are protected from diet-induced obesity due to increased thermogenesis. Under standard rodent chow or a high-fat diet, TNFR1 KO gain significantly less body mass despite increased caloric intake. Visceral adiposity and mean adipocyte diameter are reduced and blood concentrations of insulin and leptin are lower. Protection from hypothalamic leptin resistance is evidenced by increased leptin-induced suppression of food intake and preserved activation of leptin signal transduction through JAK2, STAT3, and FOXO1. Under the high-fat diet, TNFR1 KO mice present a significantly increased expression of the thermogenesis-related neurotransmitter, TRH. Further evidence of increased thermogenesis includes increased O 2 consumption in respirometry measurements, increased expressions of UCP1 and UCP3 in brown adipose tissue and skeletal muscle, respectively, and increased O 2 consumption by isolated skeletal muscle fiber mitochondria. This demonstrates that TNF-␣ signaling through TNFR1 is an important mechanism involved in obesity-associated defective thermogenesis.Obesity results from the progressive loss of the homeostatic control of food intake and energy expenditure (1, 2). High consumption of dietary fats is one of the main environmental factors contributing to the worldwide epidemic of obesity (2, 3). Fatty acids present in the diet can activate systemic and hypothalamic inflammatory signaling, which contribute to obesityassociated resistance to insulin and leptin (4, 5). Tumor necrosis factor-␣ (TNF-␣) 2 is one of the main mediators of the inflammatory response in obesity, and is expressed by infiltrating macrophages and adipocytes in the hypertrophic adipose tissue and also by microglia and neurons in the hypothalamus (4).TNF-␣ receptor 1 (TNFR1) and TNF-␣ receptor 2 (TNFR2) are the two main transducers of the TNF-␣ signals in most cells and tissues (6). The receptors share high homology in the extracellular domains, however, in the intracellular region, TNFR1 has a death domain that mediates its association with the adapter protein, TNF receptor death domain-associated protein, whereas TNFR2 has a TRAF-binding motif (7). Transducing TNF-␣ signals through either receptor results in the activation of inflammatory gene transcription by NFB and AP1 (7). In addition, under certain circumstances, pro-apoptotic stimulus can be induced by TNF-␣ (6, 7). The presence of both TNFR1 and TNFR2 are required for fu...

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Section: Discussionmentioning

confidence: 99%

Section: Experimental Model and Feeding Protocols-male Tnfrp55mentioning

confidence: 99%

Section: Experimental Model and Feeding Protocols-male Tnfrp55mentioning

confidence: 99%

See 1 more Smart Citation

Deletion of Tumor Necrosis Factor-α Receptor 1 (TNFR1) Protects against Diet-induced Obesity by Means of Increased Thermogenesis

Romanatto

Roman

Arruda

et al. 2009

Journal of Biological Chemistry

Self Cite

129

View full text Add to dashboard Cite

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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: 95%

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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“…High doses of exogenous TNF-α can reduce food intake with weight loss being proportional to the decrease of both food and water intake [26]. It needs to be noted that the effect of TNF-α on food intake is mild compared with the effects of either insulin or leptin [27]. On the contrary, hypothalamic pro-inflammatory signaling can lead to impaired insulin sensitivity [28], increasing the potential for excess weight gain [29].…”

Section: Discussionmentioning

confidence: 99%

Overnight Access to Sugar Solutions Affects mRNA Expression of Several Neuropeptides in Different Hypothalamic Regions in Rats

Zhao¹,

Campbell²,

Tschiffely³

et al. 2015

JFNR

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It has been known for years that free access to sugar solutions can cause weight gain and/or obesity in rats. We recently reported that brief access to sugar solutions can affect the hypothalamic neuropeptides that help to regulate energy balance. In this paper, we present the results in which we examined the effects of these sugars on the expression of several neuropeptides within specific hypothalamic regions. We provided Sprague Dawley rats 24 h access to 15% solutions of glucose, fructose, sucrose or high fructose corn syrup (HFCS) and then dissected portions of the paraventricular hypothalamic nuclei (PVN), the ventromedial hypothalamus (VMH) and the lateral hypothalamus (LH). We then evaluated the expression of several neuropeptides in these tissues, all of which were previously shown to be influenced by free access to sugar solutions using PCR array. Of the four sugar solutions tested, only fructose decreased expression of cholecystokinin (CCK) significantly, and only in the PVN. Glucose and sucrose significantly increased the expression of Tumor Necrosis Factor α (TNF-α) only in the PVN. Fructose and sucrose decreased Growth Hormone (GH) in the VMH. Further analysis indicated that it was fructose intake that was negatively correlated with both CCK and GH expression. Rats that had access to sugar solutions consumed less chow but maintained control levels of total caloric intake. We conclude that 24 h free access to different sugars can influence the expression of several hypothalamic neuropeptides in different ways. Changes in the expression of these neuropeptides do not disrupt total daily energy intake immediately but may nevertheless contribute to the obesity caused by long term access to sugar solutions.

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TNF-α acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient—Effects on leptin and insulin signaling pathways

Cited by 118 publications

References 35 publications

Deletion of Tumor Necrosis Factor-α Receptor 1 (TNFR1) Protects against Diet-induced Obesity by Means of Increased Thermogenesis

Deletion of Tumor Necrosis Factor-α Receptor 1 (TNFR1) Protects against Diet-induced Obesity by Means of Increased Thermogenesis

Inflammation of the Hypothalamus Leads to Defective Pancreatic Islet Function

Overnight Access to Sugar Solutions Affects mRNA Expression of Several Neuropeptides in Different Hypothalamic Regions in Rats

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