scholarly journals Disruption of Hepatocyte Jak2 leads to Spontaneous NASH in Aged Mice and Uncouples Metabolic Liver Disease from Insulin Resistance

2016 ◽  
Author(s):  
Camella G. Wilson ◽  
Aras N. Mattis ◽  
Jennifer L. Tran ◽  
Kevin Corbit ◽  
Ethan J. Weiss
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Fatty Acid ◽  
Liver Disease ◽  
Insulin Sensitivity ◽  
Growth Factor ◽  
Whole Body ◽  
Aged Mice ◽  
Age Related ◽  
Specific Deletion

ABSTRACTGrowth Hormone (GH) is a master regulator of metabolic homeostasis and longevity. Whole body GH insensitivity (GHI) augments insulin sensitivity, age-related disease resistance, adiposity, and occurrence of NAFLD. Conversely, acromegalic patients are prone to diabetes and increased mortality due to constitutive high levels of circulating GH. However, which tissues control the various metabolic aspects of GH physiology are unknown. Therefore, we determined the role of GH in age-related metabolic dysfunction by inducing hepatocyte- (JAK2L) or adipocyte-specific (JAK2A) GHI individually or combinatorially (JAK2LA) via deletion of Jak2, an obligate transducer of GH signaling. Aged JAK2L mice were insulin resistant but lean and had significant NASH, hepatic inflammation, and fibrosis. In contrast, JAK2A animals had increased adiposity and were completely resistant to age-associated hepatic steatosis, NASH, and insulin resistance. Interestingly, while JAK2LA mice retained enhanced whole-body insulin sensitivity, they still developed NASH to an almost identical degree as JAK2L mice but with a substantial reduction in the degree of microvesicular steatosis. Collectively, loss of adipocyte Jak2 conferred whole body insulin sensitivity even in the face of obesity and NASH. Deletion of hepatocyte Jak2 promoted NASH in aged mice without any dietary or drugs perturbations. The effect appears to be liver autonomous and cannot be overcome by the insulin sensitizing effect of adipocyte Jak2 deletion. Here, we describe the first model of spontaneous NASH that is coupled to augmented insulin sensitivity. Further, there was an inverse correlation between insulin sensitivity and the degree of microvesicular steatosis. Therefore, GH signaling independently mediates insulin/glucose and lipid homeostasis and directly regulates the development of NASH in aged mice.Financial Support:This study was supported by National Institutes of Health (NIH) Grants 1R01DK091276 (to E.J.W.). We also acknowledge the support of the University of California, San Francisco (UCSF) Cardiovascular Research Institute, the UCSF Diabetes Center (P30 DK063720), the UCSF Liver Center (P30 DK026743, and the James Peter Read Foundation.AbbreviationsNASHnon-alcoholic steato-hepatitisNAFLDnon-alcoholic fatty liver diseaseGHgrowth hormoneJAK2Janus kinase 2CONCON miceJAK2Lhepatocyte-specific deletion of JAK2JAK2Aadipocyte-specific deletion of JAK2JAK2LAhepatocyte and adipocyte JAK2 knockoutTGtriglycerideASTaspartate aminotransferaseALTalanine transaminaseStat5signal transducer and activator of transcription 5qRT-PCRquantitative reverse-transcription polymerase chain reactionMcp1monocyte chemoattractant protein-1Cd11bcluster of differentiation molecule 11bF4/80EGF-like module-containing mucin-like hormone receptor-like 1FcgR1high affinity immunoglobulin gamma Fc receptor IL-Fabpliver fatty acid binding proteinPPARγperoxisome proliferator-activated receptor gammaFATPfatty acid transport proteinCD36/FATFatty Acid TranslocaseITTinsulin tolerance test.Lpllipoprotein lipaseIL-interleukin-FcgR1Fc receptor IgGTnfαtumor necrosis factor alphaTgfβ1transforming growth factor beta 1αSMA, alpha 2smooth muscle actinIGF-1insulin-like growth factor 1.

scholarly journals Aging Influences the Metabolic and Inflammatory Phenotype in an Experimental Mouse Model of Acute Lung Injury

2020 ◽  
Author(s):  
Kevin W Gibbs ◽  
Chia-Chi Chuang Key ◽  
Lanazha Belfield ◽  
Jennifer Krall ◽  
Lina Purcell ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Fatty Acid ◽  
Lung Injury ◽  
Whole Body ◽  
Acid Oxidation ◽  
Aged Mice ◽  
Protein Levels ◽  
Adult Mice ◽  
Age Related ◽  
Before And After

Abstract Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 months) and aged (18–20 months) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO on survival from acute severe stress and suggesting that adult mice have increased resilience to FAO inhibition. Skeletal muscles from aged ALI mice had increased transcription of key fatty acid metabolizing enzymes, CPT-1b, LCAD, MCAD, FATP1 and UCP3. Additionally, aged mice had increased protein levels of CPT-1b at baseline and after lung injury. Surprisingly, CPT-1b in isolated skeletal muscle mitochondria had decreased activity in aged mice compared to adults. The distinct phenotype of aged ALI mice has similar characteristics to the adverse age-related outcomes of ARDS. This model may be useful to examine and augment immunologic and metabolic abnormalities unique to the critically ill aged population.

scholarly journals Growth hormone receptor antagonism with pegvisomant in insulin resistant non-diabetic men: A phase II pilot study

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 614 ◽  
Author(s):  
Ada P. Lee ◽  
Kathleen Mulligan ◽  
Morris Schambelan ◽  
Elizabeth J. Murphy ◽  
Ethan J. Weiss
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Insulin Sensitivity ◽  
Pilot Study ◽  
Glucose Metabolism ◽  
Phase Ii ◽  
Whole Body ◽  
Sensitivity Index ◽  
Insulin Resistant ◽  
Gh Receptor

Background: Growth hormone (GH) is known to affect insulin and glucose metabolism.  Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men.  Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily.  Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.

scholarly journals Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo—A Study Using the Novel PPARα/γ Agonist Tesaglitazar

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3158-3164 ◽  
Author(s):  
Bronwyn D. Hegarty ◽  
Stuart M. Furler ◽  
Nicholas D. Oakes ◽  
Edward W. Kraegen ◽  
Gregory J. Cooney
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
The Novel ◽  
High Fat

Abstract Agonists of peroxisome proliferator-activated receptors (PPARs) have emerged as important pharmacological agents for improving insulin action. A major mechanism of action of PPAR agonists is thought to involve the alteration of the tissue distribution of nonesterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly, we examined the effect of the novel PPARα/γ agonist tesaglitazar on whole-body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle, and liver in rats with dietary-induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 wk with or without treatment with tesaglitazar (1 μmol·kg−1·d−1, 7 d). NEFA clearance was measured using the partially metabolizable NEFA tracer, 3H-R-bromopalmitate, administered under conditions of basal or elevated NEFA availability. Tesaglitazar improved the insulin sensitivity of high-fat-fed rats, indicated by an increase in the glucose infusion rate during hyperinsulinemic-euglycemic clamp (P < 0.01). This improvement in insulin action was associated with decreased diglyceride (P < 0.05) and long chain acyl coenzyme A (P < 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P < 0.001). In addition the PPARα/γ agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P < 0.05). This study shows that tesaglitazar is an effective insulin-sensitizing agent in a mild dietary model of insulin resistance. Furthermore, we provide the first direct in vivo evidence that an agonist of both PPARα and PPARγ increases the ability of WAT, liver, and skeletal muscle to use fatty acids in association with its beneficial effects on insulin action in this model.

scholarly journals Central insulin‐like growth factor‐1 ( IGF ‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF ‐1 decline

Aging Cell ◽  
2015 ◽  
Vol 15 (1) ◽  
pp. 181-186 ◽  
Author(s):  
Derek M. Huffman ◽  
Gabriela Farias Quipildor ◽  
Kai Mao ◽  
Xueying Zhang ◽  
Junxiang Wan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Factor ◽  
Insulin Action ◽  
Whole Body ◽  
Insulin Like Growth Factor ◽  
Age Related

scholarly journals Prenatal and Postnatal Pathways to Obesity: Different Underlying Mechanisms, Different Metabolic Outcomes

Endocrinology ◽  
2007 ◽  
Vol 148 (5) ◽  
pp. 2345-2354 ◽  
Author(s):  
Nichola M. Thompson ◽  
Amy M. Norman ◽  
Shawn S. Donkin ◽  
Ravi R. Shankar ◽  
Mark H. Vickers ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Metabolic Regulation ◽  
Fatty Acid Synthase ◽  
Whole Body ◽  
High Fat ◽  
Metabolic Outcomes ◽  
Underlying Mechanisms ◽  
Pkc Ζ

Obesity and type 2 diabetes are worldwide health issues. The present paper investigates prenatal and postnatal pathways to obesity, identifying different metabolic outcomes with different effects on insulin sensitivity and different underlying mechanisms involving key components of insulin receptor signaling pathways. Pregnant Wistar rats either were fed chow ad libitum or were undernourished throughout pregnancy, generating either control or intrauterine growth restricted (IUGR) offspring. Male offspring were fed either standard chow or a high-fat diet from weaning. At 260 d of age, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and other metabolic parameters were measured. As expected, high-fat feeding caused diet-induced obesity (DIO) and insulin resistance. Importantly, the insulin sensitivity of IUGR offspring was similar to that of control offspring, despite fasting insulin hypersecretion and increased adiposity, irrespective of postnatal nutrition. Real-time PCR and Western blot analyses of key markers of insulin sensitivity and metabolic regulation showed that IUGR offspring had increased hepatic levels of atypical protein kinase C ζ (PKC ζ) and increased expression of fatty acid synthase mRNA. In contrast, DIO led to decreased expression of fatty acid synthase mRNA and hepatic steatosis. The decrease in hepatic PKC ζ with DIO may explain, at least in part, the insulin resistance. Our data suggest that the mechanisms of obesity induced by prenatal events are fundamentally different from those of obesity induced by postnatal high-fat nutrition. The origin of insulin hypersecretion in IUGR offspring may be independent of the mechanistic events that trigger the insulin resistance commonly observed in DIO.

scholarly journals Adipocyte JAK2 Mediates Growth Hormone-Induced Hepatic Insulin Resistance

2016 ◽  
Author(s):  
Kevin C. Corbit ◽  
João Paulo G. Camporez ◽  
Jennifer L. Tran ◽  
Camella G. Wilson ◽  
Dylan Lowe ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Metabolic Stress ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Insulin Signal Transduction ◽  
Conditional Deletion

ABSTRACTFor nearly 100 years, Growth Hormone (GH) has been known to impact insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes. Here we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extra-hepatic, adipose tissue-dependent mechanism.

Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism

2007 ◽  
Vol 292 (3) ◽  
pp. E654-E667 ◽  
Author(s):  
Dake Qi ◽  
Brian Rodrigues
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Glucose Utilization ◽  
Experimental Studies ◽  
Cardiac Metabolism ◽  
Multiple Organ ◽  
Whole Body ◽  
Metabolic Abnormalities ◽  
Organ Systems ◽  
Per Se

Insulin resistance is viewed as an insufficiency in insulin action, with glucocorticoids being recognized to play a key role in its pathogenesis. With insulin resistance, metabolism in multiple organ systems such as skeletal muscle, liver, and adipose tissue is altered. These metabolic alterations are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that metabolic abnormalities in the heart per se also play a crucial role in the development of heart failure. Following glucocorticoids, glucose utilization is compromised in the heart. This attenuated glucose metabolism is associated with altered fatty acid supply, composition, and utilization. In the heart, elevated fatty acid use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in “lipotoxicity”. In the present article, we review the action of glucocorticoids, their role in insulin resistance, and their influence in modulating peripheral and cardiac metabolism and heart disease.

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