Protein Kinase D1 Is Essential for Contraction-induced Glucose Uptake but Is Not Involved in Fatty Acid Uptake into Cardiomyocytes

Recent studies suggest that adipose tissue hypoxia (ATH) may contribute to endocrine dysfunction in adipose tissue of obese mice. In this study, we examined hypoxia's effects on metabolism in adipocytes. We determined the dynamic relationship of ATH and adiposity in ob/ob mice. The interstitial oxygen pressure (Po2) was monitored in the epididymal fat pads for ATH. During weight gain from 39.5 to 55.5 g, Po2 declined from 34.8 to 20.1 mmHg, which are 40–60% lower than those in the lean mice. Insulin receptor-β (IRβ) and insulin receptor substrate-1 (IRS-1) were decreased in the adipose tissue of obese mice, and the alteration was observed in 3T3-L1 adipocytes after hypoxia (1% oxygen) treatment. Insulin-induced glucose uptake and Akt Ser473 phosphorylation was blocked by hypoxia in the adipocytes. This effect of hypoxia exhibited cell type specificity, as it was not observed in L6 myotubes and βTC6 cells. In response to hypoxia, free fatty acid (FFA) uptake was reduced and lipolysis was increased in 3T3-L1 adipocytes. The molecular mechanism of decreased fatty acid uptake may be related to inhibition of fatty acid transporters (FATP1 and CD36) and transcription factors (PPARγ and C/EBPα) by hypoxia. The hypoxia-induced lipolysis was observed in vivo after femoral arterial clamp. Necrosis and apoptosis were induced by hypoxia in 3T3-L1 adipocytes. These data suggest that ATH may promote FFA release and inhibit glucose uptake in adipocytes by inhibition of the insulin-signaling pathway and induction of cell death.

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Involvement of atypical protein kinase C in the regulation of cardiac glucose and long-chain fatty acid uptake

Frontiers in Physiology ◽

10.3389/fphys.2012.00361 ◽

2012 ◽

Vol 3 ◽

Cited By ~ 6

Author(s):

Daphna D. J. Habets ◽

Joost J. F. P. Luiken ◽

Margriet Ouwens ◽

Will A. Coumans ◽

Monique Vergouwe ◽

...

Keyword(s):

Protein Kinase C ◽

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Uptake ◽

Chain Fatty Acid ◽

Acid Uptake ◽

Long Chain Fatty Acid ◽

Atypical Protein Kinase ◽

Kinase C ◽

Long Chain

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AMP-activated protein kinase α2 is an essential signal in the regulation of insulin-stimulated fatty acid uptake in control-fed and high-fat-fed mice

Experimental Physiology ◽

10.1113/expphysiol.2012.064402 ◽

2012 ◽

Vol 97 (5) ◽

pp. 603-617 ◽

Cited By ~ 7

Author(s):

Marcia J. Abbott ◽

Silvana Constantinescu ◽

Lorraine P. Turcotte

Keyword(s):

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

High Fat ◽

Amp Activated Protein Kinase

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Two weeks of moderate-intensity continuous training, but not high-intensity interval training, increases insulin-stimulated intestinal glucose uptake

Journal of Applied Physiology ◽

10.1152/japplphysiol.00431.2016 ◽

2017 ◽

Vol 122 (5) ◽

pp. 1188-1197 ◽

Cited By ~ 4

Author(s):

Kumail K. Motiani ◽

Anna M. Savolainen ◽

Jari-Joonas Eskelinen ◽

Jussi Toivanen ◽

Tamiko Ishizu ◽

...

Keyword(s):

Fatty Acid ◽

Free Fatty Acid ◽

Exercise Training ◽

Glucose Uptake ◽

Interval Training ◽

Fatty Acid Uptake ◽

Whole Body ◽

Moderate Intensity ◽

Acid Uptake ◽

Continuous Training

Similar to muscles, the intestine is also insulin resistant in obese subjects and subjects with impaired glucose tolerance. Exercise training improves muscle insulin sensitivity, but its effects on intestinal metabolism are not known. We studied the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on intestinal glucose and free fatty acid uptake from circulation in humans. Twenty-eight healthy, middle-aged, sedentary men were randomized for 2 wk of HIIT or MICT. Intestinal insulin-stimulated glucose uptake and fasting free fatty acid uptake from circulation were measured using positron emission tomography and [18F]FDG and [18F]FTHA. In addition, effects of HIIT and MICT on intestinal GLUT2 and CD36 protein expression were studied in rats. Training improved aerobic capacity ( P = 0.001) and whole body insulin sensitivity ( P = 0.04), but not differently between HIIT and MICT. Insulin-stimulated glucose uptake increased only after the MICT in the colon (HIIT = 0%; MICT = 37%) ( P = 0.02 for time × training) and tended to increase in the jejunum (HIIT = −4%; MICT = 13%) ( P = 0.08 for time × training). Fasting free fatty acid uptake decreased in the duodenum in both groups (HIIT = −6%; MICT = −48%) ( P = 0.001 time) and tended to decrease in the colon in the MICT group (HIIT = 0%; MICT = −38%) ( P = 0.08 for time × training). In rats, both training groups had higher GLUT2 and CD36 expression compared with control animals. This study shows that already 2 wk of MICT enhances insulin-stimulated glucose uptake, while both training modes reduce fasting free fatty acid uptake in the intestine in healthy, middle-aged men, providing an additional mechanism by which exercise training can improve whole body metabolism. NEW & NOTEWORTHY This is the first study where the effects of exercise training on the intestinal substrate uptake have been investigated using the most advanced techniques available. We also show the importance of exercise intensity in inducing these changes.

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Differential impact of adipokines derived from primary adipocytes of wild-type versus streptozotocin-induced diabetic rats on glucose and fatty acid metabolism in cardiomyocytes

Journal of Endocrinology ◽

10.1677/joe-08-0336 ◽

2008 ◽

Vol 199 (3) ◽

pp. 389-397 ◽

Cited By ~ 15

Author(s):

Rengasamy Palanivel ◽

Vivian Vu ◽

Min Park ◽

Xiangping Fang ◽

Gary Sweeney

Keyword(s):

Heart Failure ◽

Fatty Acid ◽

Glucose Uptake ◽

Conditioned Medium ◽

Fatty Acid Uptake ◽

Diabetic Rats ◽

Diabetic Rat ◽

Acid Uptake ◽

Wild Type ◽

Rat Adipocytes

The causal relationship between obesity and cardiovascular disease is extensively acknowledged; however, the exact mechanisms linking obesity and heart failure remain unclear. Here, we investigated the influence of adipokines derived from primary adipocytes on glucose and fatty acid uptake and metabolism in isolated primary cardiomyocytes. Either co-culture of these cell types or incubation with adipocyte-conditioned medium significantly increased glucose uptake in cardiomyocytes. When streptozotocin-induced diabetic rats were used as a source of adipocytes, there was a lower ability to elicit glucose uptake in cardiomyocytes which corresponded with lower Akt and AMPK phosphorylation. The profile of glucose metabolism also differed with oxidation being favored upon co-culture with wild-type adipocytes whereas lactate production was strongly induced by adipocytes from diabetic rats. Examination of fatty acid uptake revealed that stimulation only occurred in response to adipokines secreted by wild-type rat adipocytes. Importantly, oxidation of fatty acids by cardiomyocytes was decreased by adipokines derived from diabetic rat adipocytes. Analysis of adipokine profiles in diabetic rat adipocyte-conditioned medium demonstrated the most significant decreases in adiponectin and leptin with increased IL6 expression. Taken together, these data suggest that the profile of adipokines secreted by adipocytes from diabetic rats have a deleterious influence on cardiomyocyte metabolism which may be of relevance in the pathophysiology of heart failure.

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Membrane Fatty Acid Transporters as Regulators of Lipid Metabolism: Implications for Metabolic Disease

Physiological Reviews ◽

10.1152/physrev.00003.2009 ◽

2010 ◽

Vol 90 (1) ◽

pp. 367-417 ◽

Cited By ~ 421

Author(s):

Jan F. C. Glatz ◽

Joost J. F. P. Luiken ◽

Arend Bonen

Keyword(s):

Fatty Acid ◽

Glucose Uptake ◽

Contractile Activity ◽

Dynamic Properties ◽

Fatty Acid Uptake ◽

The Body ◽

Acid Uptake ◽

Membrane Fatty Acid ◽

Increase Glucose Uptake ◽

Long Chain

Long-chain fatty acids and lipids serve a wide variety of functions in mammalian homeostasis, particularly in the formation and dynamic properties of biological membranes and as fuels for energy production in tissues such as heart and skeletal muscle. On the other hand, long-chain fatty acid metabolites may exert toxic effects on cellular functions and cause cell injury. Therefore, fatty acid uptake into the cell and intracellular handling need to be carefully controlled. In the last few years, our knowledge of the regulation of cellular fatty acid uptake has dramatically increased. Notably, fatty acid uptake was found to occur by a mechanism that resembles that of cellular glucose uptake. Thus, following an acute stimulus, particularly insulin or muscle contraction, specific fatty acid transporters translocate from intracellular stores to the plasma membrane to facilitate fatty acid uptake, just as these same stimuli recruit glucose transporters to increase glucose uptake. This regulatory mechanism is important to clear lipids from the circulation postprandially and to rapidly facilitate substrate provision when the metabolic demands of heart and muscle are increased by contractile activity. Studies in both humans and animal models have implicated fatty acid transporters in the pathogenesis of diseases such as the progression of obesity to insulin resistance and type 2 diabetes. As a result, membrane fatty acid transporters are now being regarded as a promising therapeutic target to redirect lipid fluxes in the body in an organ-specific fashion.

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Arsenite Modulates Cardiac Substrate Preference by Translocation of GLUT4, But Not CD36, Independent of Mitogen-Activated Protein Kinase Signaling

Endocrinology ◽

10.1210/en.2006-0849 ◽

2006 ◽

Vol 147 (11) ◽

pp. 5205-5216 ◽

Cited By ~ 9

Author(s):

Joost J. F. P. Luiken ◽

Iman Momken ◽

Daphna D. J. Habets ◽

Mohammed El Hasnaoui ◽

Will A. Coumans ◽

...

Keyword(s):

Fatty Acid ◽

Glucose Uptake ◽

P38 Mapk ◽

Fatty Acid Uptake ◽

Chain Fatty Acid ◽

Acid Uptake ◽

Long Chain Fatty Acid ◽

P70 S6k ◽

Long Chain ◽

Stimulation Of

The protein thiol-modifying agent arsenite, a potent activator of stress signaling, was used to examine the involvement of MAPKs in the regulation of cardiac substrate uptake. Arsenite strongly induced p38 MAPK phosphorylation in isolated rat cardiac myocytes but also moderately enhanced phosphorylation of p42/44 ERK and p70 S6K. At the level of cardiomyocytic substrate use, arsenite enhanced glucose uptake dose dependently up to 5.1-fold but failed to stimulate long-chain fatty acid uptake. At the substrate transporter level, arsenite stimulated the translocation of GLUT4 to the sarcolemma but failed to recruit CD36 or FABPpm. Because arsenite did not influence the intrinsic activity of glucose transporters, GLUT4 translocation is entirely responsible for the selective increase in glucose uptake by arsenite. Moreover, the nonadditivity of arsenite-induced glucose uptake and insulin-induced glucose uptake indicates that arsenite recruits GLUT4 from insulin-responsive intracellular stores. Inhibitor studies with SB203580/SB202190, PD98059, and rapamycin indicate that activation of p38 MAPK, p42/44 ERK, and p70 S6K, respectively, are not involved in arsenite-induced glucose uptake. In addition, all these kinases do not play a role in regulation of cardiac glucose and long-chain fatty acid uptake by insulin. Hence, arsenite’s selective stimulation of glucose uptake appears unrelated to its signaling actions, suggesting that arsenite acts via thiol modification of a putative intracellular protein target of arsenite within insulin-responsive GLUT4-containing stores. Because of arsenite’s selective stimulation of cardiac glucose uptake, identification of this putative target of arsenite within the GLUT4-storage compartment may indicate whether it is a target for future strategies in prevention of diabetic cardiomyopathy.

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Exercise training improves adipose tissue metabolism and vasculature regardless of baseline glucose tolerance and sex

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000830 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000830 ◽

Cited By ~ 1

Author(s):

Sanna Maria Honkala ◽

Piryanka Motiani ◽

Riikka Kivelä ◽

Karthik Amudhala Hemanthakumar ◽

Erik Tolvanen ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Fatty Acid ◽

Glucose Tolerance ◽

Glucose Uptake ◽

Fatty Acid Uptake ◽

Moderate Intensity ◽

Acid Uptake ◽

Adipose Tissue Metabolism ◽

Tissue Metabolism

IntroductionWe investigated the effects of a supervised progressive sprint interval training (SIT) and moderate-intensity continuous training (MICT) on adipocyte morphology and adipose tissue metabolism and function; we also tested whether the responses were similar regardless of baseline glucose tolerance and sex.Research design and methods26 insulin-resistant (IR) and 28 healthy participants were randomized into 2-week-long SIT (4–6×30 s at maximum effort) and MICT (40–60 min at 60% of maximal aerobic capacity (VO2peak)). Insulin-stimulated glucose uptake and fasting-free fatty acid uptake in visceral adipose tissue (VAT), abdominal and femoral subcutaneous adipose tissues (SATs) were quantified with positron emission tomography. Abdominal SAT biopsies were collected to determine adipocyte morphology, gene expression markers of lipolysis, glucose and lipid metabolism and inflammation.ResultsTraining increased glucose uptake in VAT (p<0.001) and femoral SAT (p<0.001) and decreased fatty acid uptake in VAT (p=0.01) irrespective of baseline glucose tolerance and sex. In IR participants, training increased adipose tissue vasculature and decreased CD36 and ANGPTL4 gene expression in abdominal SAT. SIT was superior in increasing VO2peak and VAT glucose uptake in the IR group, whereas MICT reduced VAT fatty acid uptake more than SIT.ConclusionsShort-term training improves adipose tissue metabolism both in healthy and IR participants independently of the sex. Adipose tissue angiogenesis and gene expression was only significantly affected in IR participants.

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Physiological Levels of Plasma Non-Esterified Fatty Acids Impair Forearm Glucose Uptake in Normal Man

Clinical Science ◽

10.1042/cs0790167 ◽

1990 ◽

Vol 79 (2) ◽

pp. 167-174 ◽

Cited By ~ 21

Author(s):

M. Walker ◽

G. R. Fulcher ◽

C. Catalano ◽

G. Petranyi ◽

H. Orskov ◽

...

Keyword(s):

Fatty Acid ◽

Glucose Uptake ◽

Fatty Acid Uptake ◽

Whole Body ◽

Saline Control ◽

Acid Uptake ◽

Lipid Infusion ◽

Metabolite Exchange ◽

Glucose Fatty Acid Cycle ◽

And Control

1. The purpose of the present study was to maintain physiological plasma non-esterified fatty acid levels and to (i) examine their effect on skeletal muscle insulin-stimulated glucose uptake and metabolite exchange using the forearm technique, and (ii) evaluate their effect on whole-body glucose uptake and fuel oxidation. 2. Intralipid (10%) and heparin (Lipid) or saline (Control) was administered to eight healthy male subjects on separate occasions for 210 min. Insulin, glucagon and somatostatin were administered from 60 to 210 min in each study and euglycaemia was maintained. 3. Plasma non-esterified fatty acid levels plateaued at 420 ±50 μmol/l with the Lipid infusion but were completely suppressed during the Control clamp. Forearm non-esterified fatty acid uptake increased with the Lipid infusion (+ 50±10 nmol min−1 100 ml−1 of forearm) and was accompanied by a significant decrease in forearm glucose uptake (+ 3.23 ± 0.25 versus + 3.65 ± 0.35 μmol min−1 100 ml−1 of forearm, Lipid and Control, respectively; P < 0.05) and alanine release (–84±12 versus −113 ± 15 nmol min−1 100 ml−1 of forearm, Lipid and Control, respectively; P < 0.05). 4. Whole-body glucose uptake showed a comparable decrease with the Lipid infusion (6.36 ±0.81 versus 6.85±0.66 mg min−1 kg−1; P < 0.05) and was accompanied by an increase in lipid oxidation (0.33 ±0.08 versus 0.16 ±0.05 mg min−1 kg−1; P < 0.02) and a decrease in glucose oxidation (2.93 ±0.23 versus 3.30±0.20 mg min−1 kg−1; P < 0.05). 5. We conclude that the maintenance of physiological plasma non-esterified fatty acid levels is associated with a decrease in forearm and whole-body insulin-stimulated glucose uptake. The changes in substrate oxidation and forearm alanine exchange provide support for the operation of the glucose—fatty acid cycle.

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