Short-Term Manipulation of Plasma Free Fatty Acids Does Not Change Skeletal Muscle Concentrations of Ceramide and Glucosylceramide in Lean and Overweight Subjects

Abstract Context: Increased plasma free fatty acid (FFA) concentrations may be in part responsible for the increased levels of ceramide in skeletal muscle of obese subjects. Objective: We studied the effect of lowering and increasing plasma FFA levels on muscle ceramide and glucosylceramide concentrations in lean and obese subjects. Design: Plasma FFAs were either increased or decreased for 6 h by infusing a lipid emulsion or using Acipimox, respectively. Muscle biopsies were performed before and after the intervention for measurements of ceramide and glucosylceramide. Study Subjects: Eight lean [body mass index 21.9 (range, 19.6–24.6) kg/m2] and six overweight/obese [body mass index 34.4 (27.8–42.5) kg/m2] subjects without type 2 diabetes mellitus participated in the study. Main Outcome Measure: Differences in muscle ceramide and glucosylceramide upon manipulation of plasma FFAs were measured. Results: There were no differences in muscle ceramide and glucosylceramide between lean and obese subjects, respectively. Increasing or decreasing plasma FFAs for 6 h had no effect on ceramide [high FFAs: 24 (19–25) vs. 24 (22–27) pmol/mg muscle, P = 0.46; and 22 (20–28) vs. 24 (18–26) pmol/mg muscle, P = 0.89 in lean and obese, respectively; low FFAs: 26 (24–35) vs. 23 (18–27) pmol/mg muscle, P = 0.17 and 24 (15–44) vs. 24 (19–42) pmol/mg muscle, P = 0.6 in lean and obese, respectively] and glucosylceramide [high FFAs: 2.0 (1.7–4.3) vs. 3.4 (2.1–4.6) pmol/mg muscle, P = 0.17; and 3.0 (1.3–6.7) vs. 2.6 (1.2–3.9) pmol/mg muscle, P = 0.89 in lean and obese, respectively; low FFAs: 2.2 (1.0–4.4) vs. 1.7 (1.4–3.0) pmol/mg muscle, P = 0.92; and 6.6 (1.0–25.0) vs. 4.3 (1.3–7.6) pmol/mg muscle, P = 0.7 in lean and obese, respectively] concentrations in skeletal muscle. Conclusion: Short-term manipulation of plasma FFAs has no effect on ceramide and glucosylceramide concentrations in skeletal muscle from lean and obese subjects.

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A High-Fat Diet Elicits Differential Responses in Genes Coordinating Oxidative Metabolism in Skeletal Muscle of Lean and Obese Individuals

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-2253 ◽

2011 ◽

Vol 96 (3) ◽

pp. 775-781 ◽

Cited By ~ 43

Author(s):

K. E. Boyle ◽

J. P. Canham ◽

L. A. Consitt ◽

D. Zheng ◽

T. R. Koves ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Mass Index ◽

Lipid Oxidation ◽

Body Mass ◽

High Fat Diet ◽

High Fat ◽

Insulin Resistant ◽

Before And After ◽

Mrna Content ◽

Obese Subjects

Context: In lean individuals, increasing dietary lipid can elicit an increase in whole body lipid oxidation; however, with obesity the capacity to respond to changes in substrate availability appears to be compromised. Objective: To determine whether the responses of genes regulating lipid oxidation in skeletal muscle differed between lean and insulin resistant obese humans upon exposure to a high-fat diet (HFD). Design and Setting: A 5-d prospective study conducted in the research unit of an academic center. Participants: Healthy, lean (n = 12; body mass index = 22.1 ± 0.6 kg/m2), and obese (n=10; body mass index = 39.6 ± 1.7 kg/m2) males and females, between ages 18 and 30. Intervention: Participants were studied before and after a 5-d HFD (65% fat). Main Outcome Measures: Skeletal muscle biopsies (vastus lateralis) were obtained in the fasted and fed states before and after the HFD and mRNA content for genes involved with lipid oxidation determined. Skeletal muscle acylcarnitine content was determined in the fed states before and after the HFD. Results: Peroxisome proliferator activated receptor (PPAR) α mRNA content increased in lean, but not obese, subjects after a single high-fat meal. From Pre- to Post-HFD, mRNA content exhibited a body size × HFD interaction, where the lean individuals increased while the obese individuals decreased mRNA content for pyruvate dehydrogenase kinase 4, uncoupling protein 3, PPARα, and PPARγ coactivator-1α (P ≤ 0.05). In the obese subjects medium-chain acylcarnitine species tended to accumulate, whereas no change or a reduction was evident in the lean individuals. Conclusions: These findings indicate a differential response to a lipid stimulus in the skeletal muscle of lean and insulin resistant obese humans.

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Effect of β1- and β2-adrenergic stimulation on energy expenditure, substrate oxidation, and UCP3 expression in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00175.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. E775-E782 ◽

Cited By ~ 50

Author(s):

Joris Hoeks ◽

Marleen A. van Baak ◽

Matthijs K. C. Hesselink ◽

Gabby B. Hul ◽

Hubert Vidal ◽

...

Keyword(s):

Skeletal Muscle ◽

Energy Expenditure ◽

Mrna Expression ◽

Uncoupling Protein ◽

Plasma Free Fatty Acid ◽

Substrate Oxidation ◽

Mrna Levels ◽

Adrenergic Stimulation ◽

Before And After ◽

Plasma Ffa

In humans, β-adrenergic stimulation increases energy and fat metabolism. In the case of β1-adrenergic stimulation, it is fueled by an increased lipolysis. We examined the effect of β2-adrenergic stimulation, with and without a blocker of lipolysis, on thermogenesis and substrate oxidation. Furthermore, the effect of β1-and β2-adrenergic stimulation on uncoupling protein 3 (UCP3) mRNA expression was studied. Nine lean males received a 3-h infusion of dobutamine (DOB, β1) or salbutamol (SAL, β2). Also, we combined SAL with acipimox to block lipolysis (SAL+ACI). Energy and substrate metabolism were measured continuously, blood was sampled every 30 min, and muscle biopsies were taken before and after infusion. Energy expenditure significantly increased ∼13% in all conditions. Fat oxidation increased 47 ± 7% in the DOB group and 19 ± 7% in the SAL group but remained unchanged in the SAL+ACI condition. Glucose oxidation decreased 40 ± 9% upon DOB, remained unchanged during SAL, and increased 27 ± 11% upon SAL+ACI. Plasma free fatty acid (FFA) levels were increased by SAL (57 ± 11%) and DOB (47 ± 16%), whereas SAL+ACI caused about fourfold lower FFA levels compared with basal levels. No change in UCP3 was found after DOB or SAL, whereas SAL+ACI downregulated skeletal muscle UCP3 mRNA levels 38 ± 13%. In conclusion, β2-adrenergic stimulation directly increased energy expenditure independently of plasma FFA levels. Furthermore, this is the first study to demonstrate a downregulation of skeletal muscle UCP3 mRNA expression after the lowering of plasma FFA concentrations in humans, despite an increase in energy expenditure upon β2-adrenergic stimulation.

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THE BENEFIT OF SHORT-TERM WEIGHT LOSS WITH ANTI-OBESITY MEDICATIONS IN REAL-WORLD CLINICAL PRACTICE

Endocrine Practice ◽

10.4158/ep-2019-0081 ◽

2019 ◽

Vol 25 (10) ◽

pp. 1022-1028

Author(s):

Kelly Shibuya ◽

Khawla F. Ali ◽

Xinge Ji ◽

Alex Milinoivh ◽

Janine Bauman ◽

...

Keyword(s):

Body Mass Index ◽

Weight Loss ◽

Body Weight ◽

Body Mass ◽

Real World ◽

Significant Weight Loss ◽

Short Term ◽

Absolute Weight ◽

Tertiary Healthcare

Objective: The effectiveness of anti-obesity medications (AOMs) outside of clinical trials is unclear. The objective of this study was to compare the short-term effectiveness of AOMs in real-world practice. Methods: This retrospective study included adults aged ≥18 years, with body mass index ≥30 kg/m2 or ≥27 kg/m2 with at least one obesity-related comorbidity who were prescribed phentermine hydrochloride, phenterminetopiramate, bupropion-naltrexone, or lorcaserin for 12 consecutive weeks between 2006 and 2016 at a large tertiary healthcare system. Propensity score–matched cohorts were created for each pair of AOMs. The primary outcomes were percent and absolute weight loss from baseline after 12 weeks. A prediction model was constructed to estimate weight loss with different AOMs based on demographic and clinical data. Results: Of the 3,411 patients included in this study, patients lost an average of 3.45% of body weight from baseline. All AOMs were associated with a significant weight loss from baseline ( P<.0001). Patients lost the highest percentage of body weight on phentermine hydrochloride (3.75 ± 5.66%), followed by phentermine-topiramate (3.63 ± 5.7%), bupropion-naltrexone (2.66 ± 5.03%), and lorcaserin (1.84 ± 6.69%). In propensity-matched cohorts, patients taking phentermine hydrochloride lost more weight than those taking lorcaserin or bupropion-naltrexone, and patients taking phentermine topiramate lost more weight than patients taking lorcaserin. Conclusion: In real-world practice, AOMs are associated with clinically meaningful weight loss of 2 to 4% after 12 weeks. In this study, phentermine hydrochloride and phentermine topiramate produced the most weight loss. AOMs should be seriously considered as part of the armamentarium to treat patients with obesity. Abbreviations: AOM = anti-obesity medication; BMI = body mass index; EMR = electronic medical record; FDA = Food and Drug Administration; T2D = type 2 diabetes

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Pituitary-testicular axis in obese men during short-term fasting

Acta Endocrinologica ◽

10.1530/acta.0.1210727 ◽

1989 ◽

Vol 121 (5) ◽

pp. 727-732 ◽

Cited By ~ 5

Author(s):

Sven Röjdmark ◽

Anette Asplund ◽

Stephan Rössner

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Food Deprivation ◽

Obese Group ◽

Short Term ◽

Obese Subjects ◽

Normal Men

Abstract. To investigate whether short-term fasting affects the pituitary-testicular axis in obese subjects, 9 massively obese men (Body Mass Index 39.0 ± 1.3, mean± sem) were given two identical iv GnRH tests, the first (control) after an overnight fast, the second after 56 h of food deprivation. Short-term fasting augmented the GnRH-induced LH incremental area by 26%(1317±251 vs 1661 ± 297 U · 1−1 · min−1, p <0.05), but failed to affect the corresponding testosterone incremental area. Eight non-obese normal men (Body Mass Index 22.2 ± 0.5) were investigated for comparison. All of them were studied according to the same protocol as the obese group. Short-term fasting increased the GnRH-elicited LH response by 67% in the non-obese group (LH incremental areas 2147 ± 304 vs 3581 ± 256, p <0.01), and the corresponding testosterone response by 180% (testosterone incremental areas 111 ±61 vs 311±49 μg · 1−1 · min−1, p <0.01). These results imply that food deprivation affects the pituitary-testicular axis differently in obese and non-obese men.

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The effect of combination therapy of insulin glargine, metformin, and sitagliptin on insulin secretion, insulin resistance, and metabolic parameters in obese subjects with type 2 diabetes

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh1610497z ◽

2016 ◽

Vol 144 (9-10) ◽

pp. 497-502

Author(s):

Teodora Beljic-Zivkovic ◽

Milica Marjanovic-Petkovic ◽

Miljanka Vuksanovic ◽

Ivan Soldatovic ◽

Dobrila Kanlic ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Body Mass Index ◽

Waist Circumference ◽

Insulin Glargine ◽

Body Mass ◽

Fasting Glucose ◽

C Peptide ◽

Obese Subjects

Introduction. A combination of drugs is required for treatment of obese subjects with diabetes, due to multiple pathogenic mechanisms implicated in the development of both diabetes and obesity. Objective. Assessment of the effect of sitagliptin added to insulin glargine and metformin, in obese subjects with type 2 diabetes. Methods. A total of 23 obese subjects on metformin and insulin glargine participated in the study. Titration of insulin glargine during a one-month period preceded the addition of 100 mg of sitagliptin daily. Body mass index, waist circumference, fasting, and prandial glucose were measured monthly, lipids and hemoglobin A1c (HbA1c) every three months, insulin, c-peptide and glucagon at the start and after six months of treatment. Homeostatic models for insulin secretion (HOMA B) and insulin resistance (HOMA IR) were calculated. Results. Participants were 58.65 ?} 7.62 years of age with a body mass index of 35.06 ?} 5.15 kg/m2, waist circumference of 115.04 ?} 15.5 cm, and the duration of diabetes of 4.11 ?} 2.57 years. With the titration of insulin glargine, target fasting glucose levels were not achieved. Waist circumference and body mass index decreased during three months of sitagliptin treatment, thereafter remaining stable. HbA1c decreased significantly after three and six months of therapy. C-peptide increased significantly, while glucagon level fell. HOMA indexes were unchanged. Conclusion. Sitagliptin can improve diabetes control and induce modest weight loss in obese subjects poorly controlled on insulin glargine and metformin. Titration of insulin glargine to optimal fasting glucose values is a prerequisite of success of this combination therapy.

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Plasma Fatty Acids, Adiposity, and Variance of Skeletal Muscle Insulin Resistance in Type 2 Diabetes Mellitus

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.11.8027 ◽

2001 ◽

Vol 86 (11) ◽

pp. 5412-5419 ◽

Cited By ~ 38

Author(s):

David E. Kelley ◽

Katherine V. Williams ◽

Julie C. Price ◽

Therese M. McKolanis ◽

Bret H. Goodpaster ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Body Mass Index ◽

Muscle Insulin Resistance ◽

Skeletal Muscle Insulin Resistance ◽

Type 2 Dm ◽

Plasma Ffa

Skeletal muscle insulin resistance (IR) is typically severe in type 2 diabetes mellitus (DM). However, the factors that account for interindividual differences in the severity of IR are not well understood. The current study was undertaken to examine the respective roles of plasma FFA, regional adiposity, and other metabolic factors as determinants of the severity of skeletal muscle IR in type 2 DM. Twenty-three subjects (12 women and 11 men) with type 2 DM underwent positron emission tomography imaging using[ 18F]2-fluoro-2-deoxyglucose during euglycemic insulin infusions (120 mU/min·m2) to measure skeletal muscle IR, using Patlak analysis of the tissue activity curves. Body composition analysis included body mass index, fat mass, and fat-free mass by dual energy x-ray tomography, and computed tomography determinations of visceral adiposity, thigh adipose tissue distribution, and muscle composition. Body mass index, fat mass, subfascial adiposity in the thigh, and visceral adipose tissue (VAT) were all significantly related to skeletal muscle IR (r = −0.48 to −0.63; P< 0.01). However, the strongest simple correlate of IR in skeletal muscle was insulin-suppressed plasma FFA (r = −0.81; P < 0.001). VAT was the sole component of adiposity that significantly correlated with insulin-suppressed plasma FFA concentration (r = 0.64; P < 0.001). These findings indicate that the severity of skeletal muscle IR in type 2 DM is closely related to the IR of suppressing lipolysis and that plasma fatty acids and VAT are key elements mediating the link between obesity and skeletal muscle IR in type 2 DM.

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Vitamin B6 Deficiency can Reduce Fuel Storage and Utilization in Physically Trained Rats

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.78.2.64 ◽

2008 ◽

Vol 78 (2) ◽

pp. 64-69 ◽

Cited By ~ 1

Author(s):

Choi ◽

Cho

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Muscle Protein ◽

Plasma Free Fatty Acid ◽

Vitamin B ◽

Liver Protein ◽

Protein Levels ◽

Before And After ◽

Fuel Storage ◽

Exercise Muscle

This study investigated the effect of vitamin B6 deficiency on the utilization and recuperation of stored fuel in physically trained rats. 48 rats were given either vitamin B6-deficient (B6–) diet or control (B6+) diet for 4 weeks and were trained on treadmill for 30 minutes daily. All animals were then subdivided into 3 groups: before-exercise (BE); during-exercise (DE); after-exercise (AE). The DE group was exercised on treadmill for 1 hour just before being sacrificed. Animals in the AE group were allowed to take a rest for 2 hours after being exercised like the DE group. Glucose and free fatty acids were compared in plasma. Glycogen and triglyceride were compared in liver and skeletal muscle. Protein levels were compared in plasma, liver, and skeletal muscle. Compared with the B6+ group, plasma glucose levels of the B6– group were significantly lower before and after exercise. Muscle glycogen levels of the B6– group were significantly lower than those of the B6+ group regardless of exercise. The liver glycogen level of the B6– group was also significantly lower than that of B6+ group during and after exercise. Before exercise, plasma free fatty acid levels were not significantly different between the B6+ and B6– groups, and plasma free fatty acid levels of the B6– group were significantly lower during and after exercise. The muscle triglyceride level of the B6– group was significantly lower than that of the B6+ group before exercise, and there were no differences between B6+ and B6– groups during and after exercise. Liver triglyceride levels were not significantly different between B6+ and B6– groups. Plasma protein levels of the B6– group were lower than those of B6+ before and after exercise. Muscle protein levels of the B6– group were not significantly different from those of the B6+ group. Liver protein levels of the B6– group were significantly lower than that of the B6+ group after exercise. Liver protein levels of both B6+ and B6– groups were not significantly changed, regardless of exercise. Thus, it is suggested that vitamin B6 deficiency may reduce fuel storage and utilization with exercise in physically trained rats.

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