Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

Singhal, Neel S.; Lazar, Mitchell A.; Ahima, Rexford S.

doi:10.1523/jneurosci.2443-07.2007

Cited by 75 publications

(61 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In contrast, plasma levels of resistin are increased in obese insulin resistant rodents and humans (8,10,11). Unequivocally, much evidence causally links resistin to insulin resistance (8,10,11,19,20). The underlying mechanisms remain poorly characterized, particularly at the neuronal level.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, serum resistin has been positively correlated with resistin cerebrospinal fluid levels, and increased cerebrospinal fluid resistin concentrations have been associated with T2D (13). Resistin is also expressed in the hypothalamus (14), and central resistin modulates food intake and glucose and lipid metabolism (15)(16)(17)(18)(19). Interestingly, we recently reported that central resistin, via hypothalamic Toll-like receptor (TLR)4, induces overall inflammation and impairment of insulin responsiveness in rat, presenting the first evidence for the crucial role of a hypothalamic resistin-TLR4 pathway in the onset of whole-body insulin resistance and inflammation (20).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

et al. 2016

View full text Add to dashboard Cite

Adiponectin, an insulin-sensitizing hormone, and resistin, known to promote insulin resistance, constitute a potential link between obesity and type 2 diabetes. In addition, fibroblast growth factor (FGF)21 has effects similar to those of adiponectin in regulating glucose and lipid metabolism and insulin sensitivity. However, the interplay between adiponectin, FGF21, and resistin signaling pathways during the onset of insulin resistance is unknown. Here, we investigated whether central resistin promotes insulin resistance through the impairment of adiponectin and FGF21 signaling. We show that chronic intracerebroventricular resistin infusion downregulated both hypothalamic and hepatic APPL1, a key protein in adiponectin signaling, associated with decreased Akt-APPL1 interaction and an increased Akt association with its endogenous inhibitor tribbles homolog 3. Resistin treatment also decreased plasma adiponectin levels and reduced both hypothalamic and peripheral expression of adiponectin receptors. Additionally, we report that intracerebroventricular resistin increased plasma FGF21 levels and downregulated its receptor components in the hypothalamus and peripheral tissues, promoting FGF21 resistance. Interestingly, we also show that resistin effects were abolished in TLR4 knockout mice and in neuronal cells expressing TLR4 siRNAs. Our study reveals a novel mechanism of insulin resistance onset orchestrated by a central resistin-TLR4 pathway that impairs adiponectin signaling and promotes FGF21 resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

et al. 2016

View full text Add to dashboard Cite

show abstract

“…It is currently unknown which NPY receptor subtype(s) is involved in the control of metabolic processes. However, a recent study by Singhal et al (52) indicates that the Y1 receptor might be important in this respect. Because it makes sense to assume that the mechanisms regulating food intake and metabolism are tightly coupled, it is reasonable to propose that any one of the receptors involved in the control of food intake simultaneously modulates EGP.…”

Section: Diabetes Vol 57 September 2008mentioning

confidence: 98%

Intracerebroventricular Administration of Neuropeptide Y Induces Hepatic Insulin Resistance via Sympathetic Innervation

Hoek¹,

et al. 2008

View full text Add to dashboard Cite

OBJECTIVE-We recently showed that intracerebroventricular infusion of neuropeptide Y (NPY) hampers inhibition of endogenous glucose production (EGP) by insulin in mice. The downstream mechanisms responsible for these effects of NPY remain to be elucidated. Therefore, the aim of this study was to establish whether intracerebroventricular NPY administration modulates the suppressive action of insulin on EGP via hepatic sympathetic or parasympathetic innervation. RESEARCH DESIGN AND METHODS-The effects of a continuous intracerebroventricular infusion of NPY on glucose turnover were determined in rats during a hyperinsulinemiceuglycemic clamp. Either rats were sham operated, or the liver was sympathetically (hepatic sympathectomy) or parasympathetically (hepatic parasympathectomy) denervated.RESULTS-Sympathectomy or parasympathectomy did not affect the capacity of insulin to suppress EGP in intracerebroventricular vehicle-infused animals (50 Ϯ 8 vs. 49 Ϯ 6 vs. 55 Ϯ 6%, in hepatic sympathectomy vs. hepatic parasympathectomy vs. sham, respectively). Intracerebroventricular infusion of NPY significantly hampered the suppression of EGP by insulin in sham-denervated animals (29 Ϯ 9 vs. 55 Ϯ 6% for NPY/sham vs. vehicle/sham, respectively, P ϭ 0.038). Selective sympathetic denervation of the liver completely blocked the effect of intracerebroventricular NPY administration on insulin action to suppress EGP (NPY/hepatic sympathectomy, 57 Ϯ 7%), whereas selective parasympathetic denervation had no effect (NPY/hepatic parasympathectomy, 29 Ϯ 7%).CONCLUSIONS-Intracerebroventricular administration of NPY acutely induces insulin resistance of EGP via activation of sympathetic output to the liver.

show abstract

“…In a study of Singhal et al [93] the ability of resistin to increase hepatic insulin resistance and modulate the levels of various mediators in the liver was abolished in mice lacking NPY as well as in mice pretreated with icv NPY Y1 receptor antagonist. The authors established a crucial link between NPY and resistin's ability to regulate hepatic insulin resistance possibly via induction of SOCS3 (suppressor of cytokine signaling-3), tumor necrosis factor (TNF)-and interleukin 6 (IL6).…”

Section: Link Between Npy Obesity and Insulin Resistancementioning

confidence: 99%

“…The authors established a crucial link between NPY and resistin's ability to regulate hepatic insulin resistance possibly via induction of SOCS3 (suppressor of cytokine signaling-3), tumor necrosis factor (TNF)-and interleukin 6 (IL6). Additionally, NPY is critical to mediating the decrease in STAT3 (signal transducer-activated transcript-3) phosphorylation by central resistin [93].…”

Section: Link Between Npy Obesity and Insulin Resistancementioning

confidence: 99%

Appetite Regulatory Peptides and Insulin Resistance

Orbetzova¹

2012

Insulin Resistance

View full text Add to dashboard Cite

In addition to leptin and insulin, receptors for ghrelin are also located on arcuate AgRP/NPY neurons, which are activated by central ghrelin administration. Furthermore, peripheral ghrelin administration activates neurons in the ARC and AgRP and NPY have been demonstrated to be requisite mediators of the hyperphagia induced by systemic ghrelin [11]. So, meal-generated satiety signals from the GI tract do interact with longer-term adiposity signals, such as insulin and leptin in energy balance [8].NPY is one of the most abundant peptides of the hypothalamus and one of the most potent orexigenic factors. The majority of neurons expressing NPY in the hypothalamus are found within the ARC and most co-express AgRP [14]. Synthesis and release of NPY are both regulated by leptin binding to its hypothalamic receptor. NPY links afferents reflecting the nutritional status of the organism from endocrine, gastrointestinal, and central and peripheral nervous systems to effectors of energy intake and expenditure [15]. NPY stimulates appetite inducing hyperphagia, increase of fat depots, decrease of thermogenesis, and suppression of sympathetic activity. NPY is known to be involved in other physiological functions, such as cardiovascular regulation, affective disorder, memory retention, neuroendocrine control. When leptin levels increase after food intake, the latter binds to its receptors in the hypothalamus which leads to discontinuation of NPY secretion [5,16]. The decrease of NPY concentration in obesity probably plays a role of a counterregulatory factor intended to prevent further weight gain. Thus, NPY becomes one of the main regulators of food intake, body weight and energy expenditure.Ghrelin is a fast-acting hormone, seemingly playing a role in meal initiation. Secreted predominantly from the stomach, ghrelin is the natural ligand for the growth hormone secretagogue-receptor (GHS-R) in the pituitary gland, thus fulfilling the criteria of a brain- gut peptide [5,6]. Although the majority of ghrelin is produced peripherally, there are ghrelin immunoreactive neurons within the hypothalamus that have terminals on hypothalamic NPY/AgRP, POMC and corticotropin releasing hormone (CRH) neurons [17], as well as orexin fibres in the LHA [18]. It was found that ghrelin acts to promote appetite in two ways-directly, by depolarizing the orexigenic NPY/AgRP neurons, and indirectly, by increasing the tonic inhibition exerted by the NPY/AgRP neurons over the anorexigenic POMC/CART neurons. Both of these ultimately enhance appetite [4,17,18]. The ability of ghrelin to increase food intake and body weight is mediated through the stimulation of NPY production in the hypothalamic ARC, where it antagonizes the inhibitory effect on NPY secretion displayed by leptin and insulin [19].The purpose of this chapter is to provide background information on the relationship between the main appetite regulatory peptides NPY and ghrelin, and insulin resistance. The role of NPY and ghrelin in food intake and body weight control in humans, and their ...

show abstract

Central Resistin Induces Hepatic Insulin Resistance via Neuropeptide Y

Cited by 75 publications

References 51 publications

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance

Intracerebroventricular Administration of Neuropeptide Y Induces Hepatic Insulin Resistance via Sympathetic Innervation

Appetite Regulatory Peptides and Insulin Resistance

Contact Info

Product

Resources

About