Mouse Models of Insulin Resistance

Nandi, Anindita; Kitamura, Yoichi; Kahn, C. Ronald; Accili, Domenico

doi:10.1152/physrev.00032.2003

Cited by 222 publications

(180 citation statements)

References 263 publications

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“…Rather, they indicate that FGF21 improves hepatic insulin action indirectly by stimulating hepatic fatty acid disposal. Decreasing hepatic fatty acid content has well-documented effects on liver insulin sensitivity in a variety of models and indirectly improves the responsiveness of hepatic glucose production, via either glycogenolysis or gluconeogenesis (38,39). In this respect, the effects of FGF21 are analogous to those of PPAR␣ agonists, which improve hepatic insulin action and overall glycemic control in diabetic rodents despite increasing hepatic gluconeogenesis (40,41).…”

Section: Discussionmentioning

confidence: 99%

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Potthoff

Inagaki

Satapati

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

632

570

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The liver plays a crucial role in mobilizing energy during nutritional deprivation. During the early stages of fasting, hepatic glycogenolysis is a primary energy source. As fasting progresses and glycogen stores are depleted, hepatic gluconeogenesis and ketogenesis become major energy sources. Here, we show that fibroblast growth factor 21 (FGF21), a hormone that is induced in liver by fasting, induces hepatic expression of peroxisome proliferatoractivated receptor ␥ coactivator protein-1␣ (PGC-1␣), a key transcriptional regulator of energy homeostasis, and causes corresponding increases in fatty acid oxidation, tricarboxylic acid cycle flux, and gluconeogenesis without increasing glycogenolysis. Mice lacking FGF21 fail to fully induce PGC-1␣ expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis. These results reveal an unexpected relationship between FGF21 and PGC-1␣ and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation.lipid metabolism ͉ liver ͉ gluconeogenesis ͉ glycogenolysis ͉ ketogenesis I n mammals, the liver plays a crucial role in maintaining systemic energy balance during fasting and starvation through coordinate effects on carbohydrate and lipid metabolism. During the early stages of fasting, the liver mobilizes glucose from its glycogen stores. As fasting progresses and glycogen reserves are depleted, the liver oxidizes fat to provide both energy for gluconeogenesis and substrate for ketogenesis. This synchronization of hepatic lipid and carbohydrate metabolism is critical for the normal fasting response; disruption of either one of these pathways has profound effects on the other (1-4).Hormones such as glucagon, catecholamines, and glucocorticoids have important roles in controlling substrate utilization and maintaining energy balance during fasting. Recently, the hormone fibroblast growth factor 21 (FGF21) was shown to be induced in the liver during fasting (5-7). FGF21 is an unusual FGF family member in that it lacks the conventional heparinbinding domain (8) and thus can diffuse away from its tissue of origin and function as a hormone. FGF21 signals through cell-surface receptors composed of classic FGF receptors complexed with ␤-klotho, a membrane-spanning protein (9-14). Induction of FGF21 during fasting occurs through a mechanism that requires peroxisome proliferator-activated receptor ␣ (PPAR␣) (5-7). FGF21 has diverse metabolic actions that include stimulating hepatic fatty acid oxidation and ketogenesis (5,6,15) and blocking the growth hormone signaling pathway (16). FGF21 also sensitizes mice to torpor, a short-term hibernation-like state of regulated hypothermia (6). Pharmacologic administration of FGF21 to insulin-resistant rodents and monkeys improves glucose tolerance and reduces plasma insulin and triglyceride concentrations (15,17).Peroxisome proliferator-activated receptor ␥ coactivator protein-1␣ (PGC-1␣) is a transcriptional coactivator ...

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Section: Discussionmentioning

confidence: 99%

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Potthoff

Inagaki

Satapati

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

632

570

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“…Cav-1 is also downregulated since day 12, suggesting that this protein may be involved in the malfunction of the classical insulin pathway that could result in insulin resistance [18].…”

Section: Discussionmentioning

confidence: 99%

Time‐dependent regulation of muscle caveolin activation and insulin signalling in response to high‐fat diet

et al. 2009

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a b s t r a c tWe studied the effect of high-fat diet on the expression and activation of the three caveolins in rat skeletal muscle and their association with the insulin signalling cascade. Initial response was characterized by increased signalling through Cav-1 and Cav-3 phosphorylation, suggesting that both participate in an initial acute response to the calorie surplus. Afterwards, Cav-1 signalling was slightly reduced, whereas Cav-3 remained active. Late chronic phase signalling through both proteins was impaired inducing a prediabetic state. Summarizing, caveolins seem to mediate a timedependent regulation of insulin cascade in response to high-fat diet in muscle.

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“…Analysis of Irs2 -/-mice has revealed that IRS2 signals are required for proper development and function of pancreatic β-cells as well as for the central regulation of appetite (10,11). Indeed, beta cellspecific overexpression of IRS2 promotes beta cell growth, survival, and insulin secretion that prevents diabetes in Irs2 -/-, obese and streptozotocin-treated mice (12).…”

Section: Introductionmentioning

confidence: 99%

Plasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice

González-Navarro

Vila-Caballer²,

Pastor³

et al. 2007

Front Biosci

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Atherosclerosis is increased in type 2 diabetic patients but the precise mechanisms underlying this predisposition remain vague. Mice deficient for insulin receptor substrate 2 (IRS2) develop type 2-like diabetes and thus, provide a model to explore the molecular connection between deranged carbohydrate metabolism and atherosclerosis. To explore the relationship between defective insulin signalling and atherosclerosis, we have examined the development of atherosclerosis in the following groups of fat-fed mice: wild-type, diabetic Irs2-null (Irs2 -/-), atherosclerosis-prone apolipoprotein E-null (apoE -/-), and doubly-deficient apoE -/-Irs2 -/-. Surprisingly, glucose levels of apoE -/-Irs2 -/-mice were comparable to those seen in wild-type and apoE -/-and significantly lower than in Irs2 -/-mice. Irs2 -/-and apoE -/-Irs2 -/-were hyperinsulinemic compared to wild-type and apoE -/-mice. Atherosclerotic lesions were barely detectable in wild-type and Irs2 -/-mice, which displayed moderate hypercholesterolemia (~280 mg/dL). Notably, atherosclerosis was significantly enhanced in apoE -/-Irs2 -/-compared with apoE -/-mice, although both models displayed similar levels of severe hypercholesterolemia (>600 mg/dL). Circulating insulin levels predicted atherosclerotic lesion burden in apoE -/-Irs2 -/-mice. Our results suggest that hyperinsulinemia as a result of Irs2 genetic ablation contributes to increased atherosclerosis when combined with severe hypercholesterolemia (apoE -/-Irs2 -/-mice) in the absence of hyperglycaemia, thus implicating IRS2 as an important modulator of murine hypercholesterolemia-dependent atherosclerosis. Future studies are necessary to determine whether IRS2 dysfunction may promote atherosclerosis in normoglycemic, prediabetic patients with clinical manifestations of hyperinsulinemia and insulin resistance.

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Mouse Models of Insulin Resistance

Cited by 222 publications

References 263 publications

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Time‐dependent regulation of muscle caveolin activation and insulin signalling in response to high‐fat diet

Plasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice

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