The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase–leukotriene B ₄ axis

Abstract

<jats:p>Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3′-phosphoinositide–dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of insulin in adipose tissue and reduction of adipose tissue mass. A-PDK1KO mice developed insulin resistance, glucose intolerance, and hepatic steatosis, and this phenotype was suppressed by additional ablation of FoxO1 specifically in adipocytes (A-PDK1/FoxO1KO mice) without an effect on adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammatory markers in adipose tissue differed between A-PDK1KO and A-PDK1/FoxO1KO mice. Lipidomics and microarray analyses revealed that leukotriene B<jats:sub>4</jats:sub>(LTB<jats:sub>4</jats:sub>) levels in plasma and in adipose tissue as well as the expression of 5-lipoxygenase (5-LO) in adipose tissue were increased and restored in A-PDK1KO mice and A-PDK1/FoxO1KO mice, respectively. Genetic deletion of the LTB<jats:sub>4</jats:sub>receptor BLT1 as well as pharmacological intervention to 5-LO or BLT1 ameliorated insulin resistance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB<jats:sub>4</jats:sub>production through down-regulation of 5-LO expression via the PDK1−FoxO1 pathway in isolated adipocytes. Our results indicate that insulin signaling in adipocytes negatively regulates the production of LTB<jats:sub>4</jats:sub>via the PDK1−FoxO1 pathway and thereby maintains systemic insulin sensitivity.</jats:p>

Kruppel‐like factor 15 regulates fuel switching between glucose and fatty acids in brown adipocytes

“…Chromatin immunoprecipitation (ChIP) analysis was carried out with the use of a ChIP assay kit (Merck Millipore, Burlington, MA, USA) as described previously 19 . In brief, after cross‐linking with 1% formaldehyde, the nuclear fraction was isolated from differentiated HB2 cell extracts, lysed and then subjected to ultrasonic treatment to shear chromatin followed by immunoprecipitation with antibodies to KLF15 (Santa Cruz Biotechnology, Santa Cruz, CA, USA) or with control immunoglobulin G (Santa Cruz Biotechnology).…”

Inhibiting 5-lipoxygenase prevents skeletal muscle atrophy by targeting organogenesis signaling and insulin-like growth factor-1

“…E) Under atrophy-inducing conditions, such as glucocorticoid treatment or aging, catabolic signaling pathways are activated in skeletal muscle fibers, producing atrophy effector mechanisms including upregulated atrogenes expression and dysregulated autophagy. Alox5 activating protein (Alox5AP) is also known to be upregulated under atrophy-inducing conditions, and the Alox5 product, LTB4, has been shown to increase the activity of catabolic regulators, such as FoxO signaling [29-31, 38-40], which would enhance muscle fiber atrophy. F) Malotilate treatment blocks the activity of Alox5, which would reduce cellular levels of LTB4 and upregulate the expression of anti-atrophy factors, such as IGF-1, inhibiting catabolic pathways.…”

“…The increased expression of Alox5AP under conditions of atrophy could explain the effects of malotilate observed in this study. In addition, the Alox5 product, LTB4, activates the BLT1/2 G-protein coupled signaling pathway and increases the activity of NF-κb signaling in atherosclerotic plaques and FoxO signaling in adipocytes [30, 31]. NF-κb and FoxO signaling are both master regulatory pathways of skeletal muscle atrophy [32].…”

Inhibiting 5‐lipoxygenase prevents skeletal muscle atrophy by targeting organogenesis signalling and insulin‐like growth factor‐1

“…In addition, the Alox5 product, LTB 4 , activates the BLT1/2 G‐protein coupled signalling pathway and increases the activity of NF‐κb signalling in atherosclerotic plaques and FoxO signalling in adipocytes. 40 , 41 NF‐κb and FoxO signalling are both master regulatory pathways of skeletal muscle atrophy. 42 Taken together, these previous findings and the results of this study support a mechanism of action wherein atrophy conditions upregulate Alox5AP expression, which enhances the activity of Alox5 and increases LTB 4 levels.…”