Top PDF Hypothalamic resistin induces hepatic insulin resistance

Hypothalamic resistin induces hepatic insulin resistance

Hypothalamic resistin induces hepatic insulin resistance

The CNS plays a major role in the regulation of whole-body physiology. In this regard, recent evidence suggests that nutri- tional and hormonal signals originating in the brain, especially within the hypothalamus, control glucose fluxes in insulin-sensi- tive organs (53). In particular, hormones that circulate in relation to body adiposity, such as leptin and insulin, exert some of their gluco-regulatory actions through the activation of hypothalamic receptors. Based on these previous observations, we postulated that the adipose-derived hormone resistin also exerts some of its metabolic actions through a central (hypothalamic) site of action. To this end, we first investigated whether a primary increase in hypothalamic resistin per se could regulate hepatic glucose flux- es. Indeed, infusion of recombinant mouse resistin directly into the third cerebral ventricle or within the MBH of conscious rats was sufficient to recapitulate the systemic effects of resistin not only on hepatic GP but also on inflammatory mediators. This effect was verified using an additional preparation of resistin, cys, which exists only as a trimer but has previously been shown to retain full biological activity (42). Of interest, the central admin- istration of resistin markedly and selectively impaired the inhibi- tory action of insulin on hepatic glycogenolysis but failed to alter the hepatic expression of the key gluconeogenic enzymes PEPCK and G6Pase. This argues against a resistin-mediated antagonism of insulin action at the level of the hypothalamus, as intact cen- tral insulin action has been shown to be required for an insulin- induced decrease in the rate of hepatic gluconeogenesis, an effect clearly retained in these experiments (54). Thus, it is plausible that the hypothalamus-mediated effect of resistin on hepatic glu- cose flux impairs the direct (but not the hypothalamic) effects of insulin action on liver glucose fluxes. Hypothalamic resistin Figure 4
Show more

10 Read more

Activation of hypothalamic S6 kinase mediates diet induced hepatic insulin resistance in rats

Activation of hypothalamic S6 kinase mediates diet induced hepatic insulin resistance in rats

Hypothalamic overexpression of CA-S6K blunts Akt phosphorylation. After 5 h of fasting, 4 μ U insulin was infused into the MBH, and 15 min later, the MBH was harvested and analyzed. MBH lysates were blotted with anti–phospho-Thr308 and anti–phos- pho-Ser473 Akt antibodies. Results are shown as representative bands with quantitation. **P < 0.01.

11 Read more

Palmitic acid mediates hypothalamic insulin resistance by altering PKC θ subcellular localization in rodents

Palmitic acid mediates hypothalamic insulin resistance by altering PKC θ subcellular localization in rodents

i.c.v. palmitic acid (but not oleic acid) attenuates insulin-induced sup- pression of hepatic glucose production. Rats (6–8/group) received a 3-day i.c.v. infusion of palmitic acid, oleic acid, or control (cont) (PBS), before a carotid-artery insulin infusion under euglycemic clamp condi- tions. Comparable glucose use rates (~100 mg/dl) were achieved in all groups, beginning 90 minutes after the start of the experiment. All groups had plasma insulin values of approximately 900 pmol/l (data not shown). Carotid insulin infusions reduced hepatic glucose production in control and oleic acid–infused rats but not in rats infused with palmitic acid (data are mean ± SEM; ***P < 0.001 compared with control infusions).
Show more

14 Read more

Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy

Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy

The mechanism by which fat causes insulin resist- ance in human skeletal muscle remains controversial. Previous in vitro studies by Randle and colleagues have suggested that fat induces insulin resistance by increasing the NADH/NAD and fatty acyl CoA/CoA ratios, leading to a reduction in pyruvate dehydroge- nase activity and an increase in citrate concentration (24). The increase in citrate concentration leads to a decrease in phosphofructokinase activity, leading to an accumulation of glucose-6-phosphate, which in turn inhibits hexokinase. However, recent studies by our group have challenged this hypothesis and found evidence to suggest that intracellular accumulation of fatty acid–derived metabolites, such as fatty acyl CoA’s, leads to activation of protein kinase C-θ, resulting in activation of a serine/threonine cascade that leads to increased serine phosphorylation of insulin receptor substrate-1 (IRS-1). IRS-1 in turn interferes with IRS-1 tyrosine phosphorylation, resulting in decreased activation of phosphatidyli- nositol 3-kinase, a key step in activating glucose transporter-4 translocation in skeletal muscle (17, 18). Hepatic accumulation of triglyceride and fatty acid-derived metabolites is likely to cause insulin resistance in the liver by a similar mechanism. In the livers of both lipodystrophic mice (19) and transgenic mice with steatosis due to over-expression of lipopro- tein lipase (20), decreased insulin activation of IRS-2–associated phosphatidylinositol 3-kinase activity was observed. In addition, fatty acids have
Show more

7 Read more

High levels of dietary stearate promote adiposity and deteriorate hepatic insulin sensitivity

High levels of dietary stearate promote adiposity and deteriorate hepatic insulin sensitivity

The mechanistic explanation for the induction of hepatic insulin resistance by dietary stearate remains to be determined. The higher food intake in the HFL fed animals per sé may induce insulin resistance. However, no differences in food intake were found between the HFP and HFPS fed groups. As the only difference in dietary composition between these groups is stearate, these data indicate that the higher food intake in the HFL fed group are due to other components than stea- rate. In addition, these data indicate that stearate induces hepatic insulin resistance independent of food intake. In a number of studies, long chain saturated fatty acids have been shown to induce insulin resistance by activation of pathways involved in inflammation that intersect with insulin resistance such as the Toll-like receptor 4 mediated activation of NF-kB, as well as hyperphosphorylation of protein kinases like mammalian target of rapamycin (mTOR), c-jun N-terminal kinase (JNK), and protein kinase C isoforms [20-22]. A sus- tained activation of these signaling kinases has been linked to abrogation of the activation of the PI3K-PKB/ Akt pathway by insulin by inducing inhibitory serine phosphorylations on the insulin receptor and IRS1/2 [23]. The involvement of these pathways in the develop- ment of insulin resistance in the various tissues is cur- rently under investigation.
Show more

11 Read more

Adipocyte JAK2 mediates growth hormone–induced hepatic insulin resistance

Adipocyte JAK2 mediates growth hormone–induced hepatic insulin resistance

Our work relies on JAK2 as a signaling intermediate to infer GH action. While there is clear evidence that GH signaling is entirely dependent on JAK2 in fat and other tissues, it is possible or even likely that JAK2 mediates signals downstream of other cytokine signaling receptors in fat. Conditional deletion of Ghr with AP2:Cre results in obesity with no improvements in glucose homeostasis (28). Removal of Jak2 from adipose using the same Cre transgene was reported to also induce adiposity with age-related insulin resistance (39). This is in contrast to our JAK2A mice that, while obese, are exquisitely insulin sensitive, even when challenged with HFD or supraphysiologic amounts of GH. Our work here and previously (30) utilized Adiponectin:Cre, which has been shown to be considerably more adipocyte specific (40). The AP2:Cre line induces recombinase activity in the peripheral and central nervous systems as well as adre- nal medulla (41). Therefore, loss of either Ghr or Jak2 in these populations may mediate the published Figure 6. Adipocyte Jak2 mediates insulin-induced hepatic AKT activation. (A) Western blot of insulin-stimu-
Show more

15 Read more

Visceral adiposity syndrome

Visceral adiposity syndrome

Insulin resistance manifests itself differentially in vari- ous tissues, which contributes to the overall phenotype of VAS. For example, insulin resistance in: (1) WAT, results in lipolysis, increasing free fatty acids into the circula- tion, which exacerbate the deleterious cycle of hyperlipi- demia—inflammation—insulin resistance; (2) the liver, results in increased hepatic glucose production (via gly- cogenolysis and gluconeogenesis), contributing to hyper- glycemia [32]. Hepatic insulin resistance also stimulates the synthesis of hepatocyte growth factor (HGF) [36] and betatrophin [37], growth factors produced by the liver (and also by the fat tissue) that stimulate β-cell hyperpla- sia, which with other factors, such as free fat acids and glucose, contributes to the compensatory hyperinsuline- mia that often accompanies and actually worsens IR [38]; (3) skeletal muscle, a tissue with marked metabolic flex- ibility to consume and store glucose and lipids, results in increased content of free fatty acids and triglycerides [39], maintaining the vicious cycle hyperlipidemia— inflammation—insulin resistance; (4) in the central nerv- ous system (CNS), at least in animal models, results in hyperphagia and increased fat mass [40];(5) in pancre- atic β-cells results in diminished inhibition of glucagon secretion by insulin; the consequent hyperglucagonemia increases hepatic glucose production, contributing to hyperglycemia [41]; (6) in pancreatic β-cells results in reduced glucose-stimulated insulin secretion [42] and, in rodents, in lower pancreatic content of insulin [43]; (7) in the vascular endothelium results in vasoconstriction and, consequently, arterial hypertension, since insulin nor- mally induces PI3K-dependent production of nitric oxide and vasodilatation [44]; (8) in the kidney results in anti- natriuresis at several sites along the renal tubule, causing sodium retention [45] as well as in increased circulating concentrations of components of the renin-angiotension- aldosterone system [46], both changes contributing to hypertension.
Show more

8 Read more

Role of Resistin in Inflammation, Obesity and Type2 Diabetes mellitus

Role of Resistin in Inflammation, Obesity and Type2 Diabetes mellitus

Recently, it has been reported that transgenic mice over expressing resistin exhibited impaired insulin-mediated glucose transport (23). This altered glucose metabolism appeared to occur without affecting insulin receptor signalling, therefore acting by reducing the intrinsic activity of cell-surface glucose transporters (23). Lazar and co-workers (10) have recently shown resistin induced the expression of SOCS (suppressor of cytokine signalling)- 3, a known inhibitor of insulin signalling. Moreover, the loss of SOCS function was shown to impair resistin from antagonizing insulin action in adipocytes (10). This suggested that the insulin-independent action of resistin on adipocytes could partly be mediated by SOCS-3, which could have an impact on normal glucose homoeostasis (10). This worsening of glucose homoeostasis was shown to be entirely attributable to the severely impaired insulin-mediated suppression of hepatic gluconeogenesis, rather than peripheral insulin resistance (36). The study consequently suggested that fat and gut-derived resistin and RELM-β may have clear and rapid effects on stimulating the rate of hepatic glucose production, as opposed to increasing glucose uptake or influencing peripheral insulin sensitivity (36). Furthermore, this supported the notion of the existence of a feedback mechanism between adipose tissue and insulin-target organs, such as the liver. These findings have been reinforced by studies showing that the ablation of the resistin gene in mice lowering fasting glucose levels through reducing hepatic glucose production without significantly altering whole-body glucose disposal (59). This study showed that improvement in glucose homoeostasis was partly mediated via increased activation of hepatic AMPK (AMP-activated protein kinase) with reduced gene expression
Show more

10 Read more

Acute Hepatic Insulin Resistance Contributes to Hyperglycemia in Rats Following Myocardial Infarction

Acute Hepatic Insulin Resistance Contributes to Hyperglycemia in Rats Following Myocardial Infarction

That the impairment of insulin signal- ing occurs in the remote organs follow- ing MI is certainly recognized but poorly understood. Since circulating and local inflammatory cytokines are always ele- vated after MI in humans and experi- mental models (36), they may serve as important mediators of tissue-to-tissue cross-talk, which may extend beyond the injured heart to other tissues. Indeed, we found plasma TNF-α increased in MI rats. Another example for tissue-to-tissue cross-talk is cardio-renal syndromes in which MI induces decreased function in kidney (37). Thus, there are various sys- temic interactions and network in the body.
Show more

9 Read more

Role of resistin in diet induced hepatic insulin resistance

Role of resistin in diet induced hepatic insulin resistance

Epidemiological and metabolic evidence tightly links obesity to type 2 diabetes mellitus (DM2), and insulin resistance provides the strongest etiological thread (1–3). During the past decade, we have witnessed a parallel rise in the prevalence of obesity and DM2 among both children and adults (4, 5). This rapid epidemic is likely the consequence of multiple interactions between genes and environment. Consumption of high-calorie diets and seden- tary lifestyles are deemed to be the main environmental triggers (2, 4). In this regard, an understanding of the mechanisms by which these environmental factors can lead to insulin resistance is particularly important. Adipose tissue is the main endogenous source of circulating lipids, but it is also the site of production and secretion of several hormones and cytokines. These adipose- derived signaling molecules exert potent metabolic effects in dis- tant organs, and they are likely to play a key role in the complex interorgan communication network, which appears to modulate intermediate metabolism and energy balance (6, 7). Resistin is an adipose-derived circulating protein and belongs to a new gene family of small cysteine-rich secreted proteins (8). Resistin (also known as ADSF and FIZZ3) has been postulated to participate in the regulation of glucose metabolism because its administration to rodents increased blood glucose levels (9) and hepatic glucose
Show more

9 Read more

Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21

Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21

FGF21 is a complex hepatic hormone that is highly regulated by various metabolic challenges, includ- ing fasting, high-fat, low-carbohydrate, low-protein, and low–essential amino acid diets (1, 31–33). FGF21 plays an important role in coordinating the peripheral response to insulin, as genetic deletion of FGF21 leads to peripheral insulin insensitivity despite mice being normoglycemic (34). Circulating FGF21 is important for the production of adiponectin from various AT depots (35), which in turn modulates insulin sensitivity in the liver and skeletal muscle. Additionally, FGF21 signaling leads to increased glucose uptake in skeletal muscle, as well as in beige AT and bAT (28, 36). It is also required for the adaptation to cold temperature by inducing beige AT browning and increasing thermogenic potential in bAT (36, 37). In fact, serum FGF21 levels have been linked to bAT activity in lean healthy subjects (38). In addition to its effect on AT, liver-specific Fgf21 transgenic mice have lower serum insulin, cholesterol, TG, and hepatic TG levels (39). Administration of FGF21 in ob/ob mice also leads to a reduction in serum TG levels (23, 40). Similar to these reports, we also observe increased adiponectin expression, peripheral insulin sensitivity, bAT acti- vation, and peripheral tissue glucose uptake in lsTtp-KO mice compared with control mice.
Show more

17 Read more

Role of receptor for advanced glycation end products (RAGE) in liver disease

Role of receptor for advanced glycation end products (RAGE) in liver disease

driven superoxide generation in the liver of Sprague Dawley (SD) rats compared to SD rats with MCD diet alone, which were associated with severity of steatohe- patitis and hepatic fibrosis in these animals [29]. Furthermore, AGEs significantly increased reactive oxygen species (ROS) production, RAGE, monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and α-smooth muscle cell actin expression in hepatic stellate cells (HSCs) derived from MCD diet-fed rats [29]. In addition, Gaen et al. recently reported that carboxymethyllysine (CML) accumula- tion in the liver of obese individuals was associated with hepatic pro-inflammatory gene expression as well as grade of steatosis and steatohepatitis [30]. They also found that fatty acids could stimulate CML accumulation in hepatocytes and subsequently elicit inflammatory reactions via RAGE induction [30]. Lack of galectin-3, a scavenging receptor for AGEs, has been shown to progress the NAFL disease in mice, which was also associated with enhanced hepatic accu- mulation of AGEs and RAGE expression [31,32]. These findings suggest that dietary glycotoxins and/or lipid peroxidation-induced AGE accumulation in the liver might promote the progression of NAFL to NASH by enhancing the RAGE-mediated in- flammatory reactions.
Show more

7 Read more

Impaired macrophage autophagy induces systemic insulin resistance in obesity

Impaired macrophage autophagy induces systemic insulin resistance in obesity

Accumulating evidence suggests that oxidative stress along with excessive lipid accumulation in liver, adipose tissue, muscle, and pancreas is the leading cause of insulin resistance. These conditions are induced or exacerbated by overnutrition and are strongly associated with inflammation [21, 22]. For example, it has been shown that the NLRP3 inflammasome is activated by saturated free fatty acids [48] and is involved in obesity-induced inflammation and insulin resistance [49]. Accordingly, we found that Atg7KO mice displayed insulin resistance without accompanying body weight changes compared with control mice under HFD conditions. Activation of autophagy by rapamycin or resveratrol or by treating obese mice with apocynin, a ROS blocker, improved glucose homeostasis without weight loss [1, 19-22]. Hence, we hypothesize that autophagy impairment in macrophages may aggravate inflammation and ROS generation, leading to insulin resistance in Atg7KO mice, especially under HFD conditions.
Show more

15 Read more

Reversal of diet induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl CoA carboxylases 1 and 2

Reversal of diet induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl CoA carboxylases 1 and 2

enzymes with a single ASO was required to significantly reduce hepatic malonyl-CoA levels in vivo, lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides), and improve hepatic insulin sensitivity. Plasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state, indicating that lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state. These studies

9 Read more

Alshalawi

Alshalawi

Numerous potential mechanisms might assist to explain the relation between type 2 diabetes and gallbladder disease. Higher prevalence of gallbladder disease has been reported in persons with insulin resistance, obesity, metabolic syndrome, and hyperinsulinemia. 20-22 The cohabitation of these risk factors for type 2 diabetes may be the cause that participants with gallbladder disease had an increased diabetes risk. The adjustment for body mass index and waist circumference moderately attenuated the association between gallbladder disease and type 2 diabetes, suggesting that obesity might only partly explain the higher risk of type 2 diabetes in patients with gallbladder disease. 15 The present analysis recommends that a diagnosis of diabetes mellitus can increase the relative risk of gallbladder disease. Positive relations were perceived both in women and men, however, were more noticeable between American studies than in European and Asian studies, nevertheless, there were few examinations from the concluding geographic areas. The present analysis is reliable with different examinations which have discovered that the obesity, insulin resistance, metabolic disorder are related with increased gallbladder disease, as all these factors similarly are strictly associated to the risk of type 2 diabetes. 23
Show more

5 Read more

An in vivo and in vitro study of the mechanism of prednisone induced insulin resistance in healthy subjects

An in vivo and in vitro study of the mechanism of prednisone induced insulin resistance in healthy subjects

Prednisone-induced insulin resistance may depend on either reduced sensitivity (receptor defect) or reduced response to insulin (postreceptor defect). To clarify the mechanism of prednisone-induced insulin resistance, a [3H]glucose infusion (1 microCi/min) was performed for 120 min before and during a euglycemic clamp repeated at approximately 100, approximately 1,000, and approximately 10,000 microU/ml steady state plasma insulin concentration in 10 healthy, normal weight subjects, aged 35 +/- 7 yr. Each test was

8 Read more

Novel adiponectin-resistin (AR) and insulin resistance (IRAR) indexes are useful integrated diagnostic biomarkers for insulin resistance, type 2 diabetes and metabolic syndrome: a case control study

Novel adiponectin-resistin (AR) and insulin resistance (IRAR) indexes are useful integrated diagnostic biomarkers for insulin resistance, type 2 diabetes and metabolic syndrome: a case control study

Taking these studies together, adiponectin and resistin may be useful markers for insulin resistance and the variables that can integrate the abnormalities of the metabolic syndrome and cardiometabolic function. For this reason we attempted to estimate a threshold for the AR index for the identification of T2DM and MS. Although further studies may be necessary to confirm the efficacy of periodically measuring AR index in the management of insulin resistance, MS and T2DM, our study certainly highlights the potential for the AR index to move one step closer to becoming an established bio- marker of the metabolic status. The evaluation of inter- vention strategies can be facilitated and strengthened by the use of the AR index that measure biological para- meters of disease progression and therapeutic response. Routine assessment of the AR index may allow for a better understanding of the underlying disease condi- tions and optimization of anti-diabetic therapy targeting beyond simple glycemic control. Thus, the AR index has a potential for routinely available in general clinical practice and make a meaningful contribution to patient care.
Show more

18 Read more

A lipid-rich gestational diet predisposes offspring to nonalcoholic fatty liver disease: a potential sequence of events

A lipid-rich gestational diet predisposes offspring to nonalcoholic fatty liver disease: a potential sequence of events

Genistein, a soy isoflavone found in soybeans, has received more consistent favorable literature reviews than n-3 PUFAs. When provided concurrently with a maternal HF diet and comprising 0.2% (by weight) of total maternal nutrition, the offspring displayed significantly less hepatic TAG accumula- tion and elevated levels of GSH when compared to offspring that solely received a maternal HF diet. 46 As GSH produc-

9 Read more

Association of moderately elevated trimethylamine N-oxide with cardiovascular risk: is TMAO serving as a marker for hepatic insulin resistance

Association of moderately elevated trimethylamine N-oxide with cardiovascular risk: is TMAO serving as a marker for hepatic insulin resistance

In conclusion, there is a reason to suspect that the elevated risk for vascular events and type 2 diabetes associ- ated with elevated TMAO, after correction for recognised risk factors, is mediated largely by hepatic insulin resis- tance and the metabolic factors which induce it. This implies that a range of measures which typically improve hepatic insulin sensitivity, as catalogued above, could be expected to decrease elevated TMAO–a proposition that is readily clinically testable–while ameliorating the vascular and metabolic risk associated with high TMAO.
Show more

8 Read more

Gluconeogenesis and risk for fasting hyperglycemia in Black and White women

Gluconeogenesis and risk for fasting hyperglycemia in Black and White women

not differ by race. Therefore, nonhormonal factors, including mediators other than differences in ambi- ent insulin concentrations and insulin clearance, may play a primary role. Instead, racial differences in macronutrient intake and substrate oxidation could alter rates of gluconeogenesis by changing substrate availability and flux through the tricarboxylic acid cyclic (41). We evaluated and found no racial differ- ences in daily energy intake (Supplemental Table 2), daily energy expenditure (Supplemental Table 3), or energy balance (assessed by weight, Table 1). In addition, each participant received a standardized dinner meal the evening prior to the overnight fast that consisted of similar macronutrient and energy compo- sition (Black, 9 ± 0.3 kcal/kg, and White, 9.2 ± 0.2 kcal/kg, P = 0.5). Further, no differences in two key gluconeogenic substrates (lactate or glycerol concentrations) were noted between the groups. While not a gluconeogenic substrate, total FFAs tended to be lower and individual fatty acids were lower in Black women and correlated with gluconeogenesis (Figures 2 and 3). FFAs do not provide direct carbons for gluconeogenesis, but their hepatic oxidation provides the energy needed to drive gluconeogenesis, and lower FFA release from hepatic fat could reduce energy needed to drive the gluconeogenic process (42). In the setting of weight stability and similar macronutrient intake, the lower fatty acid concentrations in Black women could result from decreased FFA release or increased FFA clearance. Rates of gluconeo- genesis correlated with a marker of hepatic de novo lipogenesis, SCD-1 16 , indicating that lower hepatic stores may contribute, at least in part, to the differences in gluconeogenesis between these two groups of women. Alternatively, greater FFA clearance in Black individuals may be a consequence of relative hyper- insulinemia (as noted in this study) and has been demonstrated previously (43–47). Overall, regardless of the source (FFA release or clearance), lower fatty acid concentrations correlated with gluconeogenesis and lower basal REE. However, there was no correlation of lipid oxidation with gluconeogenesis, and when rates of gluconeogenesis were adjusted for REE, rates of gluconeogenesis were still 10% lower in Black women. Additional studies are required to determine whether variations in fatty acid availability and/or kinetics could explain the lower basal rates of gluconeogenesis observed in Black women.
Show more

14 Read more

Show all 10000 documents...

Related subjects