Publications (17) View all
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Article: Mouse skeletal muscle fiber-type-specific macroautophagy and muscle wasting are regulated by a Fyn/STAT3/Vps34 signaling pathway.
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ABSTRACT: Skeletal muscle atrophy induced by aging (sarcopenia), inactivity, and prolonged fasting states (starvation) is predominantly restricted to glycolytic type II muscle fibers and typical spares oxidative type I fibers. However, the mechanisms accounting for muscle fiber-type specificity of atrophy have remained enigmatic. In the current study, although the Fyn tyrosine kinase activated the mTORC1 signaling complex, it also induced marked atrophy of glycolytic fibers with relatively less effect on oxidative muscle fibers. This was due to inhibition of macroautophagy via an mTORC1-independent but STAT3-dependent reduction in Vps34 protein levels and decreased Vps34/p150/Beclin1/Atg14 complex 1. Physiologically, in the fed state endogenous Fyn kinase activity was increased in glycolytic but not oxidative skeletal muscle. In parallel, Y705-STAT3 phosphorylation increased with decreased Vps34 protein levels. Moreover, fed/starved regulation of Y705-STAT3 phosphorylation and Vps34 protein levels was prevented in skeletal muscle of Fyn null mice. These data demonstrate a Fyn/STAT3/Vps34 pathway that is responsible for fiber-type-specific regulation of macroautophagy and skeletal muscle atrophy.Cell reports. 05/2012; 1(5):557-69. -
Article: Dietary cholecalciferol and calcium levels in a Western-style defined rodent diet alter energy metabolism and inflammatory responses in mice.
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ABSTRACT: Male and female C57Bl6 mice were fed a control AIN76A diet, a new Western-style diet (NWD1) reflecting dietary patterns linked to elevated colon cancer incidence (higher fat, lower cholecalciferol, calcium, methyl donors, fiber), or NWD1 with elevated cholecalciferol and calcium (NWD2) from weaning. After 24 wk, serum 25-hydroxyvitamin D [25(OH)D] decreased by >80% in the NWD1 group compared with controls, but with no alteration in serum calcium or bone mineral density. The decreased serum 25(OH)D was prevented in the NWD2 group. After 32 wk, the NWD1 group compared with controls reduced overall energy expenditure by 15% without altering food consumption or physical activity and induced glucose intolerance, phenotypes associated with metabolic syndrome. These responses were unexpectedly exacerbated in the NWD2 group, further shifting mice toward greater fatty acid storage rather than oxidation compared with both control and NWD1 groups, but there was no change in physical activity, causing significant weight gain due to increased fat mass. The NWD1 group also exhibited inflammatory responses compared with controls, including macrophage-associated crown-like structures in epididymal adipose tissue and increased serum concentrations of the proinflammatory cytokine IL-1β, and of its targets, MCP-1 and Rantes, which were prevented or greatly mitigated in the NWD2 group. However, there was also elevated lipid storage in the liver and steatosis not seen in the control and NWD1 groups. Thus, elevating cholecalciferol and calcium in a Western-style diet can reduce inflammation associated with risk for colon tumor development, but interaction of nutrients in this diet can compromise liver function when fed long term.Journal of Nutrition 03/2012; 142(5):859-65. · 3.92 Impact Factor -
Article: Targeted therapies of the LKB1/AMPK pathway for the treatment of insulin resistance.
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ABSTRACT: Type II diabetes is characterized by elevated serum glucose levels and altered lipid metabolism due to peripheral insulin resistance and defects of insulin secretion in the pancreatic β-cells. While some cases of obesity and Type II diabetes result from genetic dysfunction, the increased worldwide incidence of these two disorders strongly suggest that the contribution of environmental factors such as sedentary lifestyles and high-calorie intake may disrupt energy balance. AMP-activated protein kinase and its upstream kinase liver kinase B1 are conserved serine/threonine kinases regulating anabolic and catabolic metabolic processes, therefore representing attractive therapeutic targets for the treatment of obesity and Type II diabetes. In this review, we will discuss the advantages of targeting the liver kinase B1/AMP-activated protein kinase pathway for the treatment of metabolic diseases.Future medicinal chemistry 12/2010; 2(12):1785-96. · 2.52 Impact Factor -
Article: Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation of LKB1.
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ABSTRACT: Fyn null mice display reduced adiposity associated with increased fatty acid oxidation, energy expenditure, and activation of the AMP-dependent protein kinase (AMPK) in skeletal muscle and adipose tissue. The acute pharmacological inhibition of Fyn kinase activity with SU6656 in wild-type mice reproduces these metabolic effects and induced a specific reduction in fat mass with no change in lean mass. LKB1, the main upstream AMPK kinase (AMPKK) in peripheral tissues, was redistributed from the nucleus into the cytoplasm of cells treated with SU6656 and in cells expressing a kinase-deficient, but not a constitutively kinase-active, Fyn mutant. Moreover, Fyn kinase directly phosphorylated LKB1 on tyrosine 261 and 365 residues, and mutations of these sites resulted in LKB1 export into the cytoplasm and increased AMPK phosphorylation. These data demonstrate a crosstalk between Fyn tyrosine kinase and the AMPK energy-sensing pathway, through Fyn-dependent regulation of the AMPK upstream activator LKB1.Cell metabolism 02/2010; 11(2):113-24. · 17.35 Impact Factor -
Article: Fyn kinase function in lipid utilization: a new upstream regulator of AMPK activity?
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ABSTRACT: The balance of cellular energy levels in response to changes of nutrient availability, stress stimuli or exercise is a critical step in maintaining tissue and whole body homeostasis. Disruption of this balance is associated with various pathologies, including the metabolic syndrome. Recently, accumulating evidence has demonstrated that the AMP-activated protein kinase (AMPK) plays a central role in sensing changes in energy levels. The regulation of AMPK activity is currently the subject of significant investigation since this enzyme is a potential therapeutic target in both metabolic disorders and tumorigenesis. In this review, we present novel evidence of crosstalk between Fyn, one member of the Src kinase family, and AMPK.Archives of Physiology and Biochemistry 10/2009; 115(4):191-8.
