Physical inactivity as the culprit of metabolic inflexibility: evidence from bed-rest studies

2011 ◽  
Vol 111 (4) ◽  
pp. 1201-1210 ◽  
Author(s):  
Audrey Bergouignan ◽  
Floriane Rudwill ◽  
Chantal Simon ◽  
Stéphane Blanc
Keyword(s):  
Insulin Resistance ◽  
Physical Inactivity ◽  
Metabolic Diseases ◽  
Fiber Type ◽  
Bed Rest ◽  
Sedentary Behaviors ◽  
Lipid Trafficking ◽  
Metabolic Adaptations ◽  
Physiological Adaptations ◽  
Metabolic Inflexibility

Although it is no longer debatable that sedentary behaviors are an actual cause of many metabolic diseases, the physiology of physical inactivity has been poorly investigated for this purpose. Along with microgravity, the physiological adaptations to spaceflights require metabolic adaptations to physical inactivity, and that is exceedingly well-simulated during the ground-based microgravity bed-rest analogs. Bed rest thus represents a unique model to investigate the mechanisms by which physical inactivity leads to the development of current societal chronic diseases. For decades, however, clinicians and physiologists working in space research have worked separately without taking full awareness of potential strong mutual questioning. This review summarizes the data collected over the last 60 years on metabolic adaptations to bed rest in healthy subjects. Our aim is to provide evidence that supports the hypothesis that physical inactivity per se is one of the primary causes in the development of metabolic inflexibility. This evidence will focus on four main tenants of metabolic inflexiblity: 1) insulin resistance, 2) impaired lipid trafficking and hyperlipidemia, 3) a shift in substrate use toward glucose, and 4) a shift in muscle fiber type and ectopic fat storage. Altogether, this hypothesis places sedentary behaviors upstream on the list of factors involved in metabolic inflexibility, which is considered to be a primary impairment in several metabolic disorders such as obesity, insulin resistance, and type 2 diabetes mellitus.

Effect of contrasted levels of habitual physical activity on metabolic flexibility

2013 ◽  
Vol 114 (3) ◽  
pp. 371-379 ◽  
Author(s):  
Audrey Bergouignan ◽  
Edwina Antoun ◽  
Iman Momken ◽  
Dale A. Schoeller ◽  
Guillemette Gauquelin-Koch ◽  
...  
Keyword(s):  
Physical Activity ◽  
Metabolic Diseases ◽  
Bed Rest ◽  
Normal Weight ◽  
Activity Level ◽  
Habitual Physical Activity ◽  
Metabolic Flexibility ◽  
Sedentary Behaviors ◽  
Cross Sectional ◽  
Metabolic Inflexibility

The factors regulating the body's ability to switch from fat to carbohydrate oxidation in response to fuel availability changes, or metabolic flexibility (MF), are currently intensively investigated in the context of metabolic diseases. Although numerous metabolic diseases are associated with sedentary behaviors and metabolic inflexibility, the effect of habitual physical activity level (PAL) on MF regulation is surprisingly poorly known. We investigated how PAL affects MF in cross-sectional and interventional studies. MF was assessed in 44 subjects: normal-weight and overweight sedentary men submitted to 2 mo of exercise at current recommendations, normal-weight active men submitted to 1 mo of reduced PAL and normal-weight women submitted to 1 mo of bed rest, with or without exercise. MF was evaluated, before and after interventions, following two standard meals as the relationship between individual mathematical variances in insulin and nonprotein respiratory quotient (NPRQ) daily kinetics. Daily NPRQ and insulin variances differed according to habitual PAL ( P = 0.002 and P = 0.009, respectively); active subjects had higher variances in NPRQ for lower variances in insulin than sedentary subjects, indicating a better MF. Detraining increased insulin variance ( P = 0.009) and decreased NPRQ variance ( P = 0.003), while training tended to have opposite effects. Insulin and NPRQ variances were negatively related along the PAL continuum ( R2 = 0.70, P < 0.001). Variance in NPRQ was also positively related to PAL ( R2 = 0.52, P < 0.001). By assessing MF with mathematical surrogates in conditions of daily pattern in meal's intake, we showed that habitual PAL is associated with MF status, and that MF is modulated by changes in PAL.

Metabolic disruptions induced by reduced ambulatory activity in free-living humans

2011 ◽  
Vol 111 (4) ◽  
pp. 1218-1224 ◽  
Author(s):  
John P. Thyfault ◽  
Rikke Krogh-Madsen
Keyword(s):  
Insulin Resistance ◽  
Physical Inactivity ◽  
Direct Evidence ◽  
Bed Rest ◽  
Endurance Athletes ◽  
Central Adiposity ◽  
Ambulatory Activity ◽  
Free Living ◽  
Metabolic Outcomes ◽  
Acute Responses

Physical inactivity likely plays a role in the development of insulin resistance and obesity; however, direct evidence is minimal and mechanisms of action remain unknown. Studying metabolic outcomes that occur after transitioning from higher to lower levels of physical activity is the best tool to answer these questions. Previous studies have successfully used more extreme models of inactivity, including bed rest, or the cessation of exercise in highly trained endurance athletes, to provide novel findings. However, these models do not accurately reflect the type of inactivity experienced by a large majority of the population. Recent studies have used a more applicable model in which active (∼10,000 steps/day), healthy young controls are asked to transition to an inactive lifestyle (∼1,500 steps/day) for a 14-day period. The transition to inactivity resulted in reduced insulin sensitivity and increased central adiposity. This review will discuss the outcomes of these studies, their implications for the cause/effect relationship between central adiposity and insulin resistance, and provide rationale for why inactivity induces these factors. In addition, the experimental challenges of directly linking acute responses to inactivity to chronic disease will also be discussed.

scholarly journals The effect of 8 days of strict bed rest on the incretin effect in healthy volunteers

2016 ◽  
Vol 120 (6) ◽  
pp. 608-614 ◽  
Author(s):  
Signe Tellerup Nielsen ◽  
Nina Majlund Harder-Lauridsen ◽  
Fabiana Braga Benatti ◽  
Anne-Sophie Wedell-Neergaard ◽  
Mark Preben Lyngbæk ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Physical Inactivity ◽  
Insulin Response ◽  
Bed Rest ◽  
Fat Free Mass ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Intravenous Glucose ◽  
C Peptide

Bed rest and physical inactivity are the consequences of hospital admission for many patients. Physical inactivity induces changes in glucose metabolism, but its effect on the incretin effect, which is reduced in, e.g., Type 2 diabetes, is unknown. To investigate how 8 days of strict bed rest affects the incretin effect, 10 healthy nonobese male volunteers underwent 8 days of strict bed rest. Before and after the intervention, all volunteers underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the following day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide, plasma incretin hormones [glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptide (GIP)], and serum glucagon were measured serially during both the OGTT and the IVGI. The incretin effect is calculated as the relative difference between the area under the curve for the insulin response during the OGTT and that of the corresponding IVGI, respectively. Concentrations of glucose, insulin, C-peptide, and GIP measured during the OGTT were higher after the bed rest intervention (all P < 0.05), whereas there was no difference in the levels of GLP-1 and Glucagon. Bed rest led to a mean loss of 2.4 kg of fat-free mass, and induced insulin resistance evaluated by the Matsuda index, but did not affect the incretin effect ( P = 0.6). In conclusion, 8 days of bed rest induces insulin resistance, but we did not see evidence of an associated change in the incretin effect.

scholarly journals Skeletal Muscle Mitochondria in Insulin Resistance: Differences in Intermyofibrillar Versus Subsarcolemmal Subpopulations and Relationship to Metabolic Flexibility

2011 ◽  
Vol 96 (2) ◽  
pp. 494-503 ◽  
Author(s):  
Peter Chomentowski ◽  
Paul M. Coen ◽  
Zofia Radiková ◽  
Bret H. Goodpaster ◽  
Frederico G. S. Toledo
Keyword(s):  
Insulin Resistance ◽  
Lipid Oxidation ◽  
Fiber Type ◽  
Glucose Disposal ◽  
Metabolic Flexibility ◽  
Mitochondrial Content ◽  
Insulin Resistant ◽  
Maximum Aerobic Capacity ◽  
Metabolic Inflexibility

abstract Context: Insulin resistance is accompanied by lower lipid oxidation during fasting and metabolic inflexibility. Whether these abnormalities correlate with mitochondrial content in skeletal muscle is unknown. Objective: The objective of the study was to investigate whether decreased fasting lipid oxidation, metabolic inflexibility, and impaired glucose disposal correlate with reduced mitochondrial content in intermyofibrillar vs. subsarcolemmal (SS) subpopulations. Design: Forty sedentary adults with a wide spectrum of insulin sensitivity were studied: insulin-sensitive lean subjects, insulin-resistant nondiabetic subjects, and subjects with type 2 diabetes mellitus. Glucose disposal was measured by euglycemic clamp and [6,6-D2]-glucose methodology. Fuel oxidation and metabolic flexibility (during clamps) were assessed by indirect calorimetry. Maximum aerobic capacity was assessed by treadmill testing. Intermyofibrillar and SS mitochondrial content were measured by quantitative electron microscopy of muscle biopsy samples. Results: Intermyofibrillar mitochondrial content was lower in the insulin-resistant nondiabetic subjects and type 2 diabetes mellitus groups, significantly correlating with glucose disposal in both men (R = 0.72, P &lt; 0.01) and women (R = 0.53, P &lt; 0.01). In contrast, SS mitochondrial content was similar among groups. Lower intermyofibrillar mitochondrial content was not explained by mitochondrial size, altered fiber-type distribution, or differences in maximum aerobic capacity. Intermyofibrillar mitochondrial content was significantly correlated with fasting respiratory quotient (R = −0.46, P = 0.003) and metabolic flexibility (R = 0.38, P = 0.02). Conclusions: In obese-insulin-resistant subjects with or without diabetes, intermyofibrillar mitochondrial content is decreased. This is not entirely explained by fitness status or fiber-type composition. SS mitochondrial content is unaffected, suggesting independent mitochondrial pool regulation. Lower mitochondrial content correlates with lower fasting lipid oxidation and metabolic inflexibility, suggesting it may be intrinsically linked to abnormal fuel utilization patterns of obesity-associated insulin resistance.

Insulin resistance induced by physical inactivity is associated with multiple transcriptional changes in skeletal muscle in young men

2010 ◽  
Vol 299 (5) ◽  
pp. E752-E763 ◽  
Author(s):  
A. C. Alibegovic ◽  
M. P. Sonne ◽  
L. Højbjerre ◽  
J. Bork-Jensen ◽  
S. Jacobsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Dna Methylation ◽  
Er Stress ◽  
Mitochondrial Function ◽  
Physical Inactivity ◽  
Young Men ◽  
Bed Rest ◽  
Peroxisome Proliferator ◽  
Gene Expressions ◽  
Expression Of Genes

Physical inactivity is a risk factor for insulin resistance. We examined the effect of 9 days of bed rest on basal and insulin-stimulated expression of genes potentially involved in insulin action by applying hypothesis-generating microarray in parallel with candidate gene real-time PCR approaches in 20 healthy young men. Furthermore, we investigated whether bed rest affected DNA methylation in the promoter region of the peroxisome proliferator-activated receptor-γ coactivator-1α ( PPARGC1A) gene. Subjects were reexamined after 4 wk of retraining. We found that bed rest induced insulin resistance and altered the expression of more than 4,500 genes. These changes were only partly normalized after 4 wk of retraining. Pathway analyses revealed significant downregulation of 34 pathways, predominantly those of genes associated with mitochondrial function, including PPARGC1A. Despite induction of insulin resistance, bed rest resulted in a paradoxically increased response to acute insulin stimulation in the general expression of genes, particularly those involved in inflammation and endoplasmatic reticulum (ER) stress. Furthermore, bed rest changed gene expressions of several insulin resistance and diabetes candidate genes. We also observed a trend toward increased PPARGC1A DNA methylation after bed rest. We conclude that impaired expression of PPARGC1A and other genes involved in mitochondrial function as well as a paradoxically increased response to insulin of genes involved in inflammation and ER stress may contribute to the development of insulin resistance induced by bed rest. Lack of complete normalization of changes after 4 wk of retraining underscores the importance of maintaining a minimum of daily physical activity.

Leptin responses to physical inactivity induced by simulated weightlessness

2000 ◽  
Vol 279 (3) ◽  
pp. R891-R898 ◽  
Author(s):  
Stéphane Blanc ◽  
Sylvie Normand ◽  
Christiane Pachiaudi ◽  
Monique Duvareille ◽  
Claude Gharib
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Energy Intake ◽  
Physical Inactivity ◽  
Bed Rest ◽  
Nonesterified Fatty Acid ◽  
Mass Energy ◽  
Simulated Weightlessness ◽  
Resistance Development ◽  
Glucose Ratio

Physical inactivity induced by head-down bed rest (HDBR) affects body composition (BC). Leptin is involved in BC regulation by acting on fuel homeostasis. We investigated whether leptin and counterregulatory hormone levels are affected by a 7-day HDBR. Fasting blood was sampled daily (0700) in males ( n = 8) and on alternating days in females ( n = 8) for measurements of leptin, insulin, norepinephrine (NE), epinephrine (Epi), growth hormone (GH), cortisol, nonesterified fatty acid (NEFA), and glucose. BC was measured by H2 18O dilution. Energy intake (men 10.5 ± 0.2 MJ/day, women 7.9 ± 0.3 MJ/day) and BC were unchanged by HDBR. Increased levels of leptin (men 40%, P = 0.003; women 20%, P = 0.050), insulin (men 34%, P= 0.018; women 25%, P = 0.022), and the insulin-to-glucose ratio (men 30%, P = 0.049; women 25%, P = 0.031) were noted. GH, NE, Epi, and cortisol levels were unaltered. NEFA dropped in both sexes, but glucose decreased only in women. In conclusion, HDBR increased leptin levels independently of stress response, changes in fat mass, energy intake, or gender. These changes were correlated to the insulin-resistance development in men. Further analyses are required, but the results have to be considered for longer HDBR periods with 1) the well-described drop in energy intake and 2) the BC changes.

scholarly journals Metabolic Inflexibility Is an Early Marker of Bed-Rest–Induced Glucose Intolerance Even When Fat Mass Is Stable

2018 ◽  
Vol 103 (5) ◽  
pp. 1910-1920 ◽  
Author(s):  
Floriane Rudwill ◽  
Donal O’Gorman ◽  
Etienne Lefai ◽  
Isabelle Chery ◽  
Alexandre Zahariev ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Energy Balance ◽  
Glucose Tolerance ◽  
Glucose Intolerance ◽  
Physical Inactivity ◽  
Bed Rest ◽  
Protein Supplementation ◽  
Fat Deposition ◽  
Metabolic Flexibility ◽  
Metabolic Inflexibility

Abstract Context The effects of energy-balanced bed rest on metabolic flexibility have not been thoroughly examined. Objective We investigated the effects of 21 days of bed rest, with and without whey protein supplementation, on metabolic flexibility while maintaining energy balance. We hypothesized that protein supplementation mitigates metabolic inflexibility by preventing muscle atrophy. Design and Setting Randomized crossover longitudinal study conducted at the German Aerospace Center, Cologne, Germany. Participants and Interventions Ten healthy men were randomly assigned to dietary countermeasure or isocaloric control diet during a 21-day bed rest. Outcome Measures Before and at the end of the bed rest, metabolic flexibility was assessed during a meal test. Secondary outcomes were glucose tolerance by oral glucose tolerance test, body composition by dual energy X-ray absorptiometry, ectopic fat storage by magnetic resonance imaging, and inflammation and oxidative stress markers. Results Bed rest decreased the ability to switch from fat to carbohydrate oxidation when transitioning from fasted to fed states (i.e., metabolic inflexibility), antioxidant capacity, fat-free mass (FFM), and muscle insulin sensitivity along with greater fat deposition in muscle (P &lt; 0.05 for all). Changes in fasting insulin and inflammation were not observed. However, glucose tolerance was reduced during acute overfeeding. Protein supplementation did not prevent FFM loss and metabolic alterations. Conclusions Physical inactivity triggers metabolic inflexibility, even when energy balance is maintained. Although reduced insulin sensitivity and increased fat deposition were observed at the muscle level, systemic glucose intolerance was detected only in response to a moderately high-fat meal. This finding supports the role of physical inactivity in metabolic inflexibility and suggests that metabolic inflexibility precedes systemic glucose intolerance.

Folate and vitamin B-12 deficiencies additively impaired memory function and disturbed the gut microbiota in amyloid-β infused rats

2019 ◽  
pp. 1-13 ◽  
Author(s):  
Sunmin Park ◽  
Sunna Kang ◽  
Da Sol Kim
Keyword(s):  
Insulin Resistance ◽  
Gut Microbiota ◽  
Insulin Signaling ◽  
Gut Microbiome ◽  
Metabolic Diseases ◽  
Memory Function ◽  
Amyloid Β ◽  
Impaired Memory ◽  
Ca1 Region ◽  
Folate And Vitamin B12

Abstract. Folate and vitamin B12(V-B12) deficiencies are associated with metabolic diseases that may impair memory function. We hypothesized that folate and V-B12 may differently alter mild cognitive impairment, glucose metabolism, and inflammation by modulating the gut microbiome in rats with Alzheimer’s disease (AD)-like dementia. The hypothesis was examined in hippocampal amyloid-β infused rats, and its mechanism was explored. Rats that received an amyloid-β(25–35) infusion into the CA1 region of the hippocampus were fed either control(2.5 mg folate plus 25 μg V-B12/kg diet; AD-CON, n = 10), no folate(0 folate plus 25 μg V-B12/kg diet; AD-FA, n = 10), no V-B12(2.5 mg folate plus 0 μg V-B12/kg diet; AD-V-B12, n = 10), or no folate plus no V-B12(0 mg folate plus 0 μg V-B12/kg diet; AD-FAB12, n = 10) in high-fat diets for 8 weeks. AD-FA and AD-VB12 exacerbated bone mineral loss in the lumbar spine and femur whereas AD-FA lowered lean body mass in the hip compared to AD-CON(P < 0.05). Only AD-FAB12 exacerbated memory impairment by 1.3 and 1.4 folds, respectively, as measured by passive avoidance and water maze tests, compared to AD-CON(P < 0.01). Hippocampal insulin signaling and neuroinflammation were attenuated in AD-CON compared to Non-AD-CON. AD-FAB12 impaired the signaling (pAkt→pGSK-3β) and serum TNF-α and IL-1β levels the most among all groups. AD-CON decreased glucose tolerance by increasing insulin resistance compared to Non-AD-CON. AD-VB12 and AD-FAB12 increased insulin resistance by 1.2 and 1.3 folds, respectively, compared to the AD-CON. AD-CON and Non-AD-CON had a separate communities of gut microbiota. The relative counts of Bacteroidia were lower and those of Clostridia were higher in AD-CON than Non-AD-CON. AD-FA, but not V-B12, separated the gut microbiome community compared to AD-CON and AD-VB12(P = 0.009). In conclusion, folate and B-12 deficiencies impaired memory function by impairing hippocampal insulin signaling and gut microbiota in AD rats.

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