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Article ; Online: Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance.

Ruby, Maxwell A / Massart, Julie / Hunerdosse, Devon M / Schönke, Milena / Correia, Jorge C / Louie, Sharon M / Ruas, Jorge L / Näslund, Erik / Nomura, Daniel K / Zierath, Juleen R

Cell reports

2017 Volume 18, Issue 3, Page(s) 636–646

Abstract: Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in liver biopsies from lean and obese humans in order to ... ...

Abstract	Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in liver biopsies from lean and obese humans in order to gain mechanistic insight into the pathophysiology of metabolic disease. We identified reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) in human obesity. In primary human hepatocytes, CES2 knockdown impaired glucose storage and lipid oxidation. In mice, obesity reduced CES2, whereas adenoviral delivery of human CES2 reversed hepatic steatosis, improved glucose tolerance, and decreased inflammation. Lipidomic analysis identified a network of CES2-regulated lipids altered in human and mouse obesity. CES2 possesses triglyceride and diacylglycerol lipase activities and displayed an inverse correlation with HOMA-IR and hepatic diacylglycerol concentrations in humans. Thus, decreased CES2 is a conserved feature of obesity and plays a causative role in the pathogenesis of obesity-related metabolic disturbances.
Language	English
Publishing date	2017-01-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2016.12.070
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Article ; Online: Altered intramuscular lipid metabolism relates to diminished insulin action in men, but not women, in progression to diabetes.

Perreault, Leigh / Bergman, Bryan C / Hunerdosse, Devon M / Eckel, Robert H

Obesity (Silver Spring, Md.)

2010 Volume 18, Issue 11, Page(s) 2093–2100

Abstract: Whether sex differences in intramuscular triglyceride (IMTG) metabolism underlie sex differences in the progression to diabetes are unknown. Therefore, the current study examined IMTG concentration and fractional synthesis rate (FSR) in obese men and ... ...

Abstract	Whether sex differences in intramuscular triglyceride (IMTG) metabolism underlie sex differences in the progression to diabetes are unknown. Therefore, the current study examined IMTG concentration and fractional synthesis rate (FSR) in obese men and women with normal glucose tolerance (NGT) vs. those with prediabetes (PD). PD (n = 13 men and 7 women) and NGT (n = 7 men and 12 women) groups were matched for age and anthropometry. Insulin action was quantified using a hyperinsulinemic-euglycemic clamp with infusion of [6,6-(2)H(2)]-glucose. IMTG concentration was measured by gas chromatography/mass spectrometry (GC/MS) and FSR by GC/combustion isotope ratio MS (C-IRMS), from muscle biopsies taken after infusion of [U-(13)C]palmitate during 4 h of rest. In PD men, the metabolic clearance rate (MCR) of glucose was lower during the clamp (4.71 ± 0.77 vs. 8.62 ± 1.26 ml/kg fat-free mass (FFM)/min, P = 0.04; with a trend for lower glucose rate of disappearance (Rd), P = 0.07), in addition to higher IMTG concentration (41.2 ± 5.0 vs. 21.2 ± 3.4 µg/mg dry weight, P ≤ 0.01), lower FSR (0.21 ± 0.03 vs. 0.42 ± 0.06 %/h, P ≤ 0.01), and lower oxidative capacity (P = 0.03) compared to NGT men. In contrast, no difference in Rd, IMTG concentration, or FSR was seen in PD vs. NGT women. Surprisingly, glucose Rd during the clamp was not different between NGT men and women (P = 0.25) despite IMTG concentration being higher (42.6 ± 6.1 vs. 21.2 ± 3.4 µg/mg dry weight, P = 0.03) and FSR being lower (0.23 ± 0.04 vs. 0.42 ± 0.06 %/h, P = 0.02) in women. Alterations in IMTG metabolism relate to diminished insulin action in men, but not women, in the progression toward diabetes.
MeSH term(s)	Biopsy ; Diabetes Mellitus/etiology ; Female ; Glucose Intolerance/metabolism ; Humans ; Insulin/metabolism ; Insulin Resistance ; Lipid Metabolism ; Male ; Middle Aged ; Muscle, Skeletal/metabolism ; Obesity/metabolism ; Oxidation-Reduction ; Prediabetic State/metabolism ; Sex Factors ; Triglycerides/metabolism
Chemical Substances	Insulin ; Triglycerides
Language	English
Publishing date	2010-04-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2230457-5
ISSN	1930-739X ; 1071-7323 ; 1930-7381
ISSN (online)	1930-739X
ISSN	1071-7323 ; 1930-7381
DOI	10.1038/oby.2010.76
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Article ; Online: A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation.

Bahrami-Nejad, Zahra / Zhao, Michael L / Tholen, Stefan / Hunerdosse, Devon / Tkach, Karen E / van Schie, Sabine / Chung, Mingyu / Teruel, Mary N

Cell metabolism

2018 Volume 27, Issue 4, Page(s) 854–868.e8

Abstract: Glucocorticoid and other adipogenic hormones are secreted in mammals in circadian oscillations. Loss of this circadian oscillation pattern correlates with obesity in humans, raising the intriguing question of how hormone secretion dynamics affect ... ...

Abstract	Glucocorticoid and other adipogenic hormones are secreted in mammals in circadian oscillations. Loss of this circadian oscillation pattern correlates with obesity in humans, raising the intriguing question of how hormone secretion dynamics affect adipocyte differentiation. Using live, single-cell imaging of the key adipogenic transcription factors CEBPB and PPARG, endogenously tagged with fluorescent proteins, we show that pulsatile circadian hormone stimuli are rejected by the adipocyte differentiation control system. In striking contrast, equally strong persistent signals trigger maximal differentiation. We identify the mechanism of how hormone oscillations are filtered as a combination of slow and fast positive feedback centered on PPARG. Furthermore, we confirm in mice that flattening of daily glucocorticoid oscillations significantly increases the mass of subcutaneous and visceral fat pads. Together, our study provides a molecular mechanism for why stress, Cushing's disease, and other conditions for which glucocorticoid secretion loses its pulsatility may lead to obesity.
MeSH term(s)	3T3-L1 Cells ; Adipocytes/cytology ; Adipocytes/metabolism ; Adipogenesis/genetics ; Animals ; CCAAT-Enhancer-Binding Protein-beta/metabolism ; Circadian Rhythm/genetics ; Glucocorticoids/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; PPAR gamma/metabolism ; Single-Cell Analysis ; Stromal Cells/cytology ; Stromal Cells/metabolism ; Transcription, Genetic
Chemical Substances	CCAAT-Enhancer-Binding Protein-beta ; Cebpb protein, mouse ; Glucocorticoids ; PPAR gamma
Language	English
Publishing date	2018-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2018.03.012
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Article ; Online: Chemical genetics screening reveals KIAA1363 as a cytokine-lowering target.

Hunerdosse, Devon M / Morris, Patrick J / Miyamoto, David K / Fisher, Karl J / Bateman, Leslie A / Ghazaleh, Jonathan R / Zhong, Sharon / Nomura, Daniel K

ACS chemical biology

2014 Volume 9, Issue 12, Page(s) 2905–2913

Abstract: Inflammation is a hallmark of many human diseases, including pain, arthritis, atherosclerosis, obesity and diabetes, cancer, and neurodegenerative diseases. Although there are several successfully marketed small molecules anti-inflammatory drugs such as ... ...

Abstract	Inflammation is a hallmark of many human diseases, including pain, arthritis, atherosclerosis, obesity and diabetes, cancer, and neurodegenerative diseases. Although there are several successfully marketed small molecules anti-inflammatory drugs such as cyclooxygenase inhibitors and glucocorticoids, many of these compounds are also associated with various adverse cardiovascular or immunosuppressive side effects. Thus, identifying novel anti-inflammatory small molecules and their targets is critical for developing safer and more effective next-generation treatment strategies for inflammatory diseases. Here, we have conducted a chemical genetics screen to identify small molecules that suppress the release of the inflammatory cytokine TNFα from stimulated macrophages. We have used an enzyme class-directed chemical library for our screening efforts to facilitate subsequent target identification using activity-based protein profiling (ABPP). Using this strategy, we have found that KIAA1363 is a novel target for lowering key pro-inflammatory cytokines through affecting key ether lipid metabolism pathways. Our study highlights the application of combining chemical genetics with chemoproteomic and metabolomic approaches toward identifying and characterizing anti-inflammatory smal molecules and their targets.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/chemical synthesis ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacology ; Carboxylic Ester Hydrolases/antagonists & inhibitors ; Carboxylic Ester Hydrolases/genetics ; Carboxylic Ester Hydrolases/metabolism ; Cell Line ; Cytokines/antagonists & inhibitors ; Cytokines/biosynthesis ; Gene Expression Regulation ; High-Throughput Screening Assays ; Humans ; Inflammation/drug therapy ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/pathology ; Lipid Metabolism/drug effects ; Lipopolysaccharides/pharmacology ; Macrophage Activation/drug effects ; Macrophages/cytology ; Macrophages/drug effects ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Primary Cell Culture ; Signal Transduction ; Small Molecule Libraries/pharmacology ; Sterol Esterase/antagonists & inhibitors ; Sterol Esterase/genetics ; Sterol Esterase/metabolism ; Structure-Activity Relationship
Chemical Substances	Anti-Inflammatory Agents ; Cytokines ; Lipopolysaccharides ; Small Molecule Libraries ; Carboxylic Ester Hydrolases (EC 3.1.1.-) ; Nceh1 protein, mouse (EC 3.1.1.-) ; NCEH1 protein, human (EC 3.1.1.13) ; Sterol Esterase (EC 3.1.1.13)
Language	English
Publishing date	2014-11-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/cb500717g
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Article ; Online: Fenofibrate administration does not affect muscle triglyceride concentration or insulin sensitivity in humans.

Perreault, Leigh / Bergman, Bryan C / Hunerdosse, Devon M / Howard, David J / Eckel, Robert H

Metabolism: clinical and experimental

2011 Volume 60, Issue 8, Page(s) 1107–1114

Abstract: ... 0.4 ×10(-4)/ μU/mL, W vs M, P < .01) at baseline despite similar IMTG concentration (41.9 ± 15.5 vs ... 30.8 ± 5.1 μg/mg dry weight, W vs M, P = .43) and IMTG fractional synthesis rate (FSR) (0.27%/h ± 0 ... 07%/h vs 0.35%/h ± 0.06%/h, W vs M, P = .41) as men. Fenofibrate enhanced FSR in men (0.35 ± 0.06 ...

Abstract	Animal data suggest that males, in particular, rely on peroxisome proliferator activated receptor-α activity to maintain normal muscle triglyceride metabolism. We sought to examine whether this was also true in men vs women and its relationship to insulin sensitivity (Si). Normolipidemic obese men (n = 9) and women (n = 9) underwent an assessment of Si (intravenous glucose tolerance test) and intramuscular triglyceride (IMTG) metabolism (gas chromatography/mass spectrometry and gas chromatography-combustion isotope ratio mass spectrometry from plasma and muscle biopsies taken after infusion of [U-(13)C]palmitate) before and after 12 weeks of fenofibrate treatment. Women were more insulin sensitive (Si: 5.2 ± 0.7 vs 2.4 ± 0.4 ×10(-4)/ μU/mL, W vs M, P < .01) at baseline despite similar IMTG concentration (41.9 ± 15.5 vs 30.8 ± 5.1 μg/mg dry weight, W vs M, P = .43) and IMTG fractional synthesis rate (FSR) (0.27%/h ± 0.07%/h vs 0.35%/h ± 0.06%/h, W vs M, P = .41) as men. Fenofibrate enhanced FSR in men (0.35 ± 0.06 to 0.54 ± 0.06, P = .05), with no such change seen in women (0.27 ± 0.07 to 0.32 ± 0.13, P = .73) and no change in IMTG concentration in either group (23.0 ± 3.9 in M, P = .26 vs baseline; 36.3 ± 12.0 in W, P = .79 vs baseline). Insulin sensitivity was unaffected by fenofibrate (P ≥ .68). Lower percentage saturation of IMTG in women vs men before (29.1% ± 2.3% vs 35.2% ± 1.7%, P = .06) and after (27.3% ± 2.8% vs 35.1% ± 1.9%, P = .04) fenofibrate most closely related to their greater Si (R(2) = 0.34, P = .10) and was largely unchanged by the drug. Peroxisome proliferator activated receptor-α agonist therapy had little effect on IMTG metabolism in men or women. Intramuscular triglyceride saturation, rather than IMTG concentration or FSR, most closely (but not significantly) related to Si and was unchanged by fenofibrate administration.
MeSH term(s)	Aged ; Blood Glucose/metabolism ; Body Composition ; Female ; Fenofibrate/pharmacology ; Glucose Tolerance Test ; Humans ; Hypolipidemic Agents/pharmacology ; Insulin/metabolism ; Insulin Resistance/physiology ; Male ; Middle Aged ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Overweight/metabolism ; Triglycerides/metabolism
Chemical Substances	Blood Glucose ; Hypolipidemic Agents ; Insulin ; Triglycerides ; Fenofibrate (U202363UOS)
Language	English
Publishing date	2011-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80230-x
ISSN	1532-8600 ; 0026-0495
ISSN (online)	1532-8600
ISSN	0026-0495
DOI	10.1016/j.metabol.2010.12.003
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Article ; Online: Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance

Maxwell A. Ruby / Julie Massart / Devon M. Hunerdosse / Milena Schönke / Jorge C. Correia / Sharon M. Louie / Jorge L. Ruas / Erik Näslund / Daniel K. Nomura / Juleen R. Zierath

Cell Reports, Vol 18, Iss 3, Pp 636-

2017 Volume 646

Abstract	Serine hydrolases are a large family of multifunctional enzymes known to influence obesity. Here, we performed activity-based protein profiling to assess the functional level of serine hydrolases in liver biopsies from lean and obese humans in order to gain mechanistic insight into the pathophysiology of metabolic disease. We identified reduced hepatic activity of carboxylesterase 2 (CES2) and arylacetamide deacetylase (AADAC) in human obesity. In primary human hepatocytes, CES2 knockdown impaired glucose storage and lipid oxidation. In mice, obesity reduced CES2, whereas adenoviral delivery of human CES2 reversed hepatic steatosis, improved glucose tolerance, and decreased inflammation. Lipidomic analysis identified a network of CES2-regulated lipids altered in human and mouse obesity. CES2 possesses triglyceride and diacylglycerol lipase activities and displayed an inverse correlation with HOMA-IR and hepatic diacylglycerol concentrations in humans. Thus, decreased CES2 is a conserved feature of obesity and plays a causative role in the pathogenesis of obesity-related metabolic disturbances.
Keywords	obesity ; hepatic steatosis ; carboxylesterase ; lipidomics ; insulin resistance ; activity-based protein profiling ; inflammation ; diacylglycerol ; serine hydrolase ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Incretin action maintains insulin secretion, but not hepatic insulin action, in people with impaired fasting glucose.

Perreault, Leigh / Man, Chiara Dalla / Hunerdosse, Devon M / Cobelli, Claudio / Bergman, Bryan C

Diabetes research and clinical practice

2010 Volume 90, Issue 1, Page(s) 87–94

Abstract: Aims: To determine whether altered GLP-1 activity contributes to the abnormal endogenous glucose production (EGP) and insulin secretion characteristic of people with impaired fasting glucose (IFG).: Methods: People with IFG (n=10) and normal glucose ... ...

Abstract	Aims: To determine whether altered GLP-1 activity contributes to the abnormal endogenous glucose production (EGP) and insulin secretion characteristic of people with impaired fasting glucose (IFG). Methods: People with IFG (n=10) and normal glucose tolerance (NGT; n=13) underwent assessment of EGP (via [6,6-(2)H(2)]-glucose infusion). Parameters of whole body insulin action and secretion were estimated by IVGTT and OGTT. Measures of EGP and insulin secretion were made before and after sitagliptin administration. Results: EGP was not different at baseline (glucose R(a); 1.47+/-0.08 vs. 1.46+/-0.05mg/kg/min, IFG vs. NGT, p=0.93). However, when differences in circulating insulin were accounted for (EGPXSSPI; 20.2+/-2.1 vs. 14.4+/-1.0AU, vs. NGT, p=0.03) the hepatic insulin resistance index was significantly higher in IFG. Baseline insulin action (S(i); 2.3+/-0.1x10(-4)/microU/ml vs. 3.5+/-0.4x10(-4)/microU/ml, p=0.01, IFG vs. NGT) and secretion (DI; 587+/-81x10(-4)/min vs. 1171+/-226x10(-4)/min, p=0.04, IFG vs. NGT) were impaired in IFG when evaluated by the IVGTT, but not by OGTT (insulin sensitivity 4.52+/-1.08x10(-4)dl/kg/min vs. 6.73+/-1.16x10(-4)dl/kg/min, IFG vs. NGT, p=0.16; indices of basal (Phi(b)), static (Phi(s)), dynamic (Phi(d)), and total (Phi(t)) insulin secretion, p>0.07). Sitagliptin did not change EGP or insulin secretion in either group. Conclusions: Incretin action maintained insulin secretion, but not hepatic insulin action, in people with IFG.
MeSH term(s)	Aged ; Blood Glucose/analysis ; Body Mass Index ; C-Peptide/blood ; Dipeptidyl-Peptidase IV Inhibitors/adverse effects ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Female ; Glucagon-Like Peptide 1/blood ; Glucagon-Like Peptide 1/physiology ; Glucose/chemistry ; Glucose/pharmacokinetics ; Glucose Tolerance Test ; Humans ; Hyperglycemia/blood ; Hyperglycemia/drug therapy ; Incretins/blood ; Incretins/physiology ; Insulin/blood ; Insulin/metabolism ; Insulin Resistance ; Insulin Secretion ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Liver/drug effects ; Liver/physiopathology ; Male ; Middle Aged ; Pyrazines/adverse effects ; Pyrazines/therapeutic use ; Severity of Illness Index ; Sitagliptin Phosphate ; Triazoles/adverse effects ; Triazoles/therapeutic use
Chemical Substances	Blood Glucose ; C-Peptide ; Dipeptidyl-Peptidase IV Inhibitors ; Incretins ; Insulin ; Pyrazines ; Triazoles ; Glucagon-Like Peptide 1 (89750-14-1) ; Glucose (IY9XDZ35W2) ; Sitagliptin Phosphate (TS63EW8X6F)
Language	English
Publishing date	2010-08-13
Publishing country	Ireland
Document type	Controlled Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	632523-3
ISSN	1872-8227 ; 0168-8227
ISSN (online)	1872-8227
ISSN	0168-8227
DOI	10.1016/j.diabres.2010.06.012
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Article ; Online: Intramuscular triglyceride synthesis: importance in muscle lipid partitioning in humans.

Bergman, Bryan C / Perreault, Leigh / Strauss, Allison / Bacon, Samantha / Kerege, Anna / Harrison, Kathleen / Brozinick, Joseph T / Hunerdosse, Devon M / Playdon, Mary C / Holmes, William / Bui, Hai Hoang / Sanders, Phil / Siddall, Parker / Wei, Tao / Thomas, Melissa K / Kuo, Ming Shang / Eckel, Robert H

American journal of physiology. Endocrinology and metabolism

2017 Volume 314, Issue 2, Page(s) E152–E164

Abstract: Intramuscular triglyceride (IMTG) concentration is elevated in insulin-resistant individuals and was once thought to promote insulin resistance. However, endurance-trained athletes have equivalent concentration of IMTG compared with individuals with type ...

Abstract	Intramuscular triglyceride (IMTG) concentration is elevated in insulin-resistant individuals and was once thought to promote insulin resistance. However, endurance-trained athletes have equivalent concentration of IMTG compared with individuals with type 2 diabetes, and have very low risk of diabetes, termed the "athlete's paradox." We now know that IMTG synthesis is positively related to insulin sensitivity, but the exact mechanisms for this are unclear. To understand the relationship between IMTG synthesis and insulin sensitivity, we measured IMTG synthesis in obese control subjects, endurance-trained athletes, and individuals with type 2 diabetes during rest, exercise, and recovery. IMTG synthesis rates were positively related to insulin sensitivity, cytosolic accumulation of DAG, and decreased accumulation of C18:0 ceramide and glucosylceramide. Greater rates of IMTG synthesis in athletes were not explained by alterations in FFA concentration, DGAT1 mRNA expression, or protein content. IMTG synthesis during exercise in Ob and T2D indicate utilization as a fuel despite unchanged content, whereas IMTG concentration decreased during exercise in athletes. mRNA expression for genes involved in lipid desaturation and IMTG synthesis were increased after exercise and recovery. Further, in a subset of individuals, exercise decreased cytosolic and membrane di-saturated DAG content, which may help explain insulin sensitization after acute exercise. These data suggest IMTG synthesis rates may influence insulin sensitivity by altering intracellular lipid localization, and decreasing specific ceramide species that promote insulin resistance.
MeSH term(s)	Adult ; Athletes ; Biological Transport ; Case-Control Studies ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/physiopathology ; Exercise/physiology ; Female ; Humans ; Insulin Resistance/physiology ; Lipid Metabolism/physiology ; Lipogenesis/physiology ; Male ; Muscle, Skeletal/metabolism ; Obesity/complications ; Obesity/metabolism ; Obesity/physiopathology ; Physical Endurance/physiology ; Rest ; Triglycerides/metabolism
Chemical Substances	Triglycerides
Language	English
Publishing date	2017-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603841-4
ISSN	1522-1555 ; 0193-1849
ISSN (online)	1522-1555
ISSN	0193-1849
DOI	10.1152/ajpendo.00142.2017
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Article ; Online: Novel and reversible mechanisms of smoking-induced insulin resistance in humans.

Bergman, Bryan C / Perreault, Leigh / Hunerdosse, Devon / Kerege, Anna / Playdon, Mary / Samek, Ali M / Eckel, Robert H

Diabetes

2012 Volume 61, Issue 12, Page(s) 3156–3166

Abstract: Smoking is the most common cause of preventable morbidity and mortality in the United States, in part because it is an independent risk factor for the development of insulin resistance and type 2 diabetes. However, mechanisms responsible for smoking- ... ...

Abstract	Smoking is the most common cause of preventable morbidity and mortality in the United States, in part because it is an independent risk factor for the development of insulin resistance and type 2 diabetes. However, mechanisms responsible for smoking-induced insulin resistance are unclear. In this study, we found smokers were less insulin sensitive compared with controls, which increased after either 1 or 2 weeks of smoking cessation. Improvements in insulin sensitivity after smoking cessation occurred with normalization of IRS-1(ser636) phosphorylation. In muscle cell culture, nicotine exposure significantly increased IRS-1(ser636) phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. The two pathways known to stimulate IRS-1(ser636) phosphorylation (p44/42 mitogen-activated protein kinase [MAPK] and mammalian target of rapamycin [mTOR]) were both stimulated by nicotine in culture. Inhibition of mTOR, but not p44/42 MAPK, during nicotine exposure prevented IRS-1(ser636) phosphorylation and normalized insulin sensitivity. These data indicate nicotine induces insulin resistance in skeletal muscle by activating mTOR. Therapeutic agents designed to oppose skeletal muscle mTOR activation may prevent insulin resistance in humans who are unable to stop smoking or are chronically exposed to secondhand smoke.
MeSH term(s)	Adult ; Blotting, Western ; Female ; Humans ; Insulin Receptor Substrate Proteins/genetics ; Insulin Receptor Substrate Proteins/metabolism ; Insulin Resistance/genetics ; Insulin Resistance/physiology ; Male ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/metabolism ; Nicotine/pharmacology ; Phosphorylation/drug effects ; Smoking/adverse effects ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; Young Adult
Chemical Substances	IRS1 protein, human ; Insulin Receptor Substrate Proteins ; Nicotine (6M3C89ZY6R) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
Language	English
Publishing date	2012-09-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db12-0418
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Article ; Online: Inflexibility in intramuscular triglyceride fractional synthesis distinguishes prediabetes from obesity in humans.

Perreault, Leigh / Bergman, Bryan C / Hunerdosse, Devon M / Playdon, Mary C / Eckel, Robert H

Obesity (Silver Spring, Md.)

2009 Volume 18, Issue 8, Page(s) 1524–1531

Abstract: Whether intramuscular triglyceride (IMTG) concentration or flux is more important in the progression to type 2 diabetes is controversial. Therefore, this study examined IMTG concentration, as well as its fractional synthesis rate (FSR), in obese people ... ...

Abstract	Whether intramuscular triglyceride (IMTG) concentration or flux is more important in the progression to type 2 diabetes is controversial. Therefore, this study examined IMTG concentration, as well as its fractional synthesis rate (FSR), in obese people with normal glucose tolerance (NGT; n = 20) vs. obese people with prediabetes (PD; n = 19), at rest and during exercise. Insulin action and secretion were assessed using an intravenous glucose tolerance test. [U-(13)C]palmitate was infused for 4 h before and throughout 1.5 h of treadmill walking at 50% VO(2(max)). IMTG concentration was measured by gas chromatograph/mass spectrometer, and FSR by gas chromatography-combustion isotope ratio mass spectrometer, from muscle biopsies taken immediately before and after exercise. Basal IMTG concentration was higher (43 +/- 5.7 vs. 27 +/- 3.9 mg/mg dry weight, P = 0.03) and FSR trended lower (0.23 +/- 0.04 vs. 0.32 +/- 0.05/h, P = 0.075), as did insulin action (S(i); 2.9 +/- 0.43 vs. 3.3 +/- 0.35 x 10(-4)/mU/ml, P = 0.07), in PD vs. NGT. IMTG concentration did not change significantly during exercise, but was no longer different in PD vs. NGT (45 +/- 7.7 vs. 37 +/- 5.8 mg/mg dry weight, P = 0.41). IMTG FSR suppressed during exercise in NGT (-81% to 0.06 +/- 0.13/h, P = 0.02), but not PD (+4% to 0.24 +/- 0.13%/h, P = 0.95). Palmitate oxidation was similar during rest (P = 0.92) and exercise (P = 0.94) between groups, but its source appeared different with more coming from muscle at rest and plasma during exercise in NGT, whereas the converse was true in PD. Altogether, higher basal IMTG concentration that is metabolically inflexible distinguishes obese people with PD from those with NGT.
MeSH term(s)	Aged ; Dietary Fats/administration & dosage ; Dietary Fats/metabolism ; Exercise/physiology ; Female ; Glucose Intolerance/metabolism ; Glucose Tolerance Test ; Humans ; Insulin/metabolism ; Male ; Middle Aged ; Muscle, Skeletal/metabolism ; Obesity/metabolism ; Oxidation-Reduction ; Palmitates/metabolism ; Prediabetic State/metabolism ; Triglycerides/metabolism
Chemical Substances	Dietary Fats ; Insulin ; Palmitates ; Triglycerides
Language	English
Publishing date	2009-12-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2230457-5
ISSN	1930-739X ; 1071-7323 ; 1930-7381
ISSN (online)	1930-739X
ISSN	1071-7323 ; 1930-7381
DOI	10.1038/oby.2009.454
Database	MEDical Literature Analysis and Retrieval System OnLINE

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