Both moderate- and high-intensity exercise training increase intramyocellular lipid droplet abundance and modify myocellular distribution in adults with obesity.

Exercise training modifies lipid metabolism in skeletal muscle, but the effect of exercise training on intramyocellular lipid droplet (LD) abundance, size, and intracellular distribution in adults with obesity remains elusive. This study compared high-intensity interval training (HIIT) with more conventional moderate-intensity continuous training (MICT) on intramyocellular lipid content, as well as LD characteristics (size and number) and abundance within the intramyofibrillar (IMF) and subsarcolemmal (SS) regions of type I and type II skeletal muscle fibers in adults with obesity. Thirty-six adults with obesity [body mass index (BMI) = 33 ± 3 kg/m2] completed 12 wk (4 days/wk) of either HIIT (10 × 1 min, 90% HRmax + 1-min active recovery; n = 19) or MICT (45-min steady-state exercise, 70% HRmax; n = 17), while on a weight-maintaining diet throughout training. Skeletal muscle biopsies were collected from the vastus lateralis before and after training, and intramyocellular lipid content and intracellular LD distribution were measured by immunofluorescence microscopy. Both MICT and HIIT increased total intramyocellular lipid content by more than 50% (P < 0.01), which was attributed to a greater LD number per µm2 in the IMF region of both type I and type II muscle fibers (P < 0.01). Our findings also suggest that LD lipophagy (autophagy-mediated LD degradation) may be transiently upregulated the day after the last exercise training session (P < 0.02 for both MICT and HIIT). In summary, exercise programs for adults with obesity involving either MICT or HIIT increased skeletal muscle LD abundance via a greater number of LDs in the IMF region of the myocyte, thereby providing more lipid in close proximity to the site of energy production during exercise.NEW & NOTEWORTHY In this study, 12 wk of either moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) enhanced skeletal muscle lipid abundance by increasing lipid droplet number within the intramyofibrillar (IMF) region of muscle. Because the IMF associates with high energy production during muscle contraction, this adaptation may enhance lipid oxidation during exercise. Despite differences in training intensity and energy expenditure between MICT and HIIT, their effects on muscle lipid abundance and metabolism were remarkably similar.

Metabolic dysfunction in obesity is related to impaired suppression of fatty acid release from adipose tissue by insulin.

OBJECTIVE: The aims of this study were: 1) to assess relationships among insulin-mediated glucose uptake with standard clinical outcomes and deep-phenotyping measures (including fatty acid [FA] rate of appearance [FA Ra] into the systemic circulation); and 2) to examine the contribution of adipocyte size, fibrosis, and proteomic profile to FA Ra regulation. METHODS: A total of 66 adults with obesity (BMI = 34 [SD 3] kg/m2 ) were assessed for insulin sensitivity (hyperinsulinemic-euglycemic clamp), and stable isotope dilution methods quantified glucose, FA, and glycerol kinetics in vivo. Abdominal subcutaneous adipose tissue (aSAT) and skeletal muscle biopsies were collected, and magnetic resonance imaging quantified liver and visceral fat content. RESULTS: Insulin-mediated FA Ra suppression associated with insulin-mediated glucose uptake (r = 0.51; p < 0.01) and negatively correlated with liver (r = -0.36; p < 0.01) and visceral fat (r = -0.42; p < 0.01). aSAT proteomics from subcohorts of participants with low FA Ra suppression (n = 8) versus high FA Ra suppression (n = 8) demonstrated greater extracellular matrix collagen protein in low versus high FA Ra suppression. Skeletal muscle lipidomics (n = 18) revealed inverse correlations of FA Ra suppression with acyl-chain length of acylcarnitine (r = -0.42; p = 0.02) and triacylglycerol (r = -0.51; p < 0.01), in addition to insulin-mediated glucose uptake (acylcarnitine: r = -0.49; p < 0.01, triacylglycerol: r = -0.40; p < 0.01). CONCLUSIONS: Insulin's ability to suppress FA release from aSAT in obesity is related to enhanced insulin-mediated glucose uptake and metabolic health in peripheral tissues.

One week of overeating upregulates angiogenic and lipolytic gene expression in human subcutaneous adipose tissue from exercise trained and untrained adults.

Effective storage of excess energy in abdominal subcutaneous adipose tissue during periods of overeating may help attenuate weight-gain-related insulin resistance. The objective of this study was to assess changes in the expression of factors regulating abdominal subcutaneous adipose tissue storage capacity in response to a brief exposure to overeating in nonobese adults. Because exercise can alter the expression of genes involved in regulating adipose tissue storage capacity, we compared the responses to overeating in regular exercisers (EX, n = 11) and nonexercisers (nonEX, n = 11). Abdominal subcutaneous adipose tissue samples and oral glucose tolerance tests were performed before and after participants ate 30% above their estimated daily energy requirements for 1 week. Both EX and nonEX gained ∼1 kg (P < 0.01), and Matsuda insulin sensitivity index was reduced ∼15% (P = 0.04) in both groups. Gene expression of factors involved in lipid metabolism (HSL, ATGL, DGAT, and PPARγ) and angiogenesis (HIF1α and KDR) were increased (P < 0.05), with no differences observed between EX and nonEX. In contrast, protein abundance of these factors did not change. The modest overeating stimulus did not increase markers of inflammation in the systemic circulation or adipose tissue. Overall, our findings indicate that a brief and modest overeating stimulus can impair insulin sensitivity and upregulate genes involved in abdominal adipose tissue storage capacity similarly in exercisers and nonexercisers. ClinicalTrials.gov ID#: NCT02701738.

Exercise training remodels subcutaneous adipose tissue in adults with obesity even without weight loss.

Excessive adipose tissue mass underlies much of the metabolic health complications in obesity. Although exercise training is known to improve metabolic health in individuals with obesity, the effects of exercise training without weight loss on adipose tissue structure and metabolic function remain unclear. Thirty-six adults with obesity (body mass index = 33 ± 3 kg · m-2 ) were assigned to 12 weeks (4 days week-1 ) of either moderate-intensity continuous training (MICT; 70% maximal heart rate, 45 min; n = 17) or high-intensity interval training (HIIT; 90% maximal heart rate, 10 × 1 min; n = 19), maintaining their body weight throughout. Abdominal subcutaneous adipose tissue (aSAT) biopsy samples were collected once before and twice after training (1 day after last exercise and again 4 days later). Exercise training modified aSAT morphology (i.e. reduced fat cell size, increased collagen type 5a3, both P ≤ 0.05, increased capillary density, P = 0.05) and altered protein abundance of factors that regulate aSAT remodelling (i.e. reduced matrix metallopeptidase 9; P = 0.02; increased angiopoietin-2; P < 0.01). Exercise training also increased protein abundance of factors that regulate lipid metabolism (e.g. hormone sensitive lipase and fatty acid translocase; P ≤ 0.03) and key proteins involved in the mitogen-activated protein kinase pathway when measured the day after the last exercise session. However, most of these exercise-mediated changes were no longer significant 4 days after exercise. Importantly, MICT and HIIT induced remarkably similar adaptations in aSAT. Collectively, even in the absence of weight loss, 12 weeks of exercise training induced changes in aSAT structure, as well as factors that regulate metabolism and the inflammatory signal pathway in adults with obesity. KEY POINTS: Exercise training is well-known to improve metabolic health in obesity, although how exercise modifies the structure and metabolic function of adipose tissue, in the absence of weight loss, remains unclear. We report that both 12 weeks of moderate-intensity continuous training (MICT) and 12 weeks of high-intensity interval training (HIIT) induced modifications in adipose tissue structure and factors that regulate adipose tissue remodelling, metabolism and the inflammatory signal pathway in adults with obesity, even without weight loss (with no meaningful differences between MICT and HIIT). The modest modifications in adipose tissue structure in response to 12 weeks of MICT or HIIT did not lead to changes in the rate of fatty acid release from adipose tissue. These results expand our understanding about the effects of two commonly used exercise training prescriptions (MICT and HIIT) on adipose tissue remodelling that may lead to advanced strategies for improving metabolic health outcomes in adults with obesity.

The hepatokine TSK maintains myofiber integrity and exercise endurance and contributes to muscle regeneration.

Mammalian skeletal muscle contains heterogenous myofibers with different contractile and metabolic properties that sustain muscle mass and endurance capacity. The transcriptional regulators that govern these myofiber gene programs have been elucidated. However, the hormonal cues that direct the specification of myofiber types and muscle endurance remain largely unknown. Here, we uncover the secreted factor Tsukushi (TSK) as an extracellular signal that is required for maintaining muscle mass, strength, and endurance capacity and that contributes to muscle regeneration. Mice lacking TSK exhibited reduced grip strength and impaired exercise capacity. Muscle transcriptomic analysis revealed that TSK deficiency results in a remarkably selective impairment in the expression of myofibrillar genes, characteristic of slow-twitch muscle fibers, that is associated with abnormal neuromuscular junction formation. AAV-mediated overexpression of TSK failed to rescue these myofiber defects in adult mice, suggesting that the effects of TSK on myofibers are likely restricted to certain developmental stages. Finally, mice lacking TSK exhibited diminished muscle regeneration following cardiotoxin-induced muscle injury. These findings support a crucial role of TSK as a hormonal cue in the regulation of contractile gene expression, endurance capacity, and muscle regeneration.

Exercise training decreases whole-body and tissue iron storage in adults with obesity.

NEW FINDINGS: What is the central question of this study? Does exercise training modify tissue iron storage in adults with obesity? What is the main finding and its importance? Twelve weeks of moderate-intensity exercise or high-intensity interval training lowered whole-body iron stores, decreased the abundance of the key iron storage protein in skeletal muscle (ferritin) and tended to lower hepatic iron content. These findings show that exercise training can reduce tissue iron storage in adults with obesity and might have important implications for obese individuals with dysregulated iron homeostasis. ABSTRACT: The regulation of iron storage is crucial to human health, because both excess and deficient iron storage have adverse consequences. Recent studies suggest altered iron storage in adults with obesity, with increased iron accumulation in their liver and skeletal muscle. Exercise training increases iron use for processes such as red blood cell production and can lower whole-body iron stores in humans. However, the effects of exercise training on liver and muscle iron stores in adults with obesity have not been assessed. The aim of this study was to determine the effects of 12 weeks of exercise training on whole-body iron stores, liver iron content and the abundance of ferritin (the key iron storage protein) in skeletal muscle in adults with obesity. Twenty-two inactive adults (11 women and 11 men; age, 31 ± 6 years; body mass index, 33 ± 3 kg/m2 ) completed 12 weeks (four sessions/week) of either moderate-intensity continuous training (MICT; 45 min at 70% of maximal heart rate; n = 11) or high-intensity interval training (HIIT; 10 × 1 min at 90% of maximal heart rate, interspersed with 1 min active recovery; n = 11). Whole-body iron stores were lower after training, as indicated by decreased plasma concentrations of ferritin (P = 3 × 10-5 ) and hepcidin (P = 0.02), without any change in C-reactive protein. Hepatic R2*, an index of liver iron content, was 6% lower after training (P = 0.06). Training reduced the skeletal muscle abundance of ferritin by 10% (P = 0.03), suggesting lower muscle iron storage. Interestingly, these adaptations were similar in MICT and HIIT groups. Our findings indicate that exercise training decreased iron storage in adults with obesity, which might have important implications for obese individuals with dysregulated iron homeostasis.

Skeletal muscle ferritin abundance is tightly related to plasma ferritin concentration in adults with obesity.

NEW FINDINGS: What is the central question of this study? Obesity is associated with complex perturbations to iron homeostasis: is plasma ferritin concentration (a biomarker of whole-body iron stores) related to the abundance of ferritin (the key tissue iron storage protein) in skeletal muscle in adults with obesity? What is the main finding and its importance? Plasma ferritin concentration was tightly correlated with the abundance of ferritin in skeletal muscle, and this relationship persisted when accounting for sex, age, body mass index and plasma C-reactive protein concentration. Our findings suggest that skeletal muscle may be an important iron store. ABSTRACT: Obesity is associated with complex perturbations to whole-body and tissue iron homeostasis. Recent evidence suggests a potentially important influence of iron storage in skeletal muscle on whole-body iron homeostasis, but this association is not clearly resolved. The primary aim of this study was to assess the relationship between whole-body and skeletal muscle iron stores by measuring the abundance of the key iron storage (ferritin) and import (transferrin receptor) proteins in skeletal muscle, as well as markers of whole-body iron homeostasis in men (n = 19) and women (n = 43) with obesity. Plasma ferritin concentration (a marker of whole-body iron stores) was highly correlated with muscle ferritin abundance (r = 0.77, P = 2 × 10-13 ) and negatively associated with muscle transferrin receptor abundance (r = -0.76, P = 1 × 10-12 ). These relationships persisted when accounting for sex, age, BMI and plasma C-reactive protein concentration. In parallel with higher whole-body iron stores in our male versus female participants, men had 2.2-fold higher muscle ferritin abundance (P = 1 × 10-4 ) compared with women. In accordance with lower muscle iron storage, women had 2.7-fold higher transferrin receptor abundance (P = 7 × 10-10 ) compared with men. We conclude that muscle iron storage and import proteins are tightly and independently related to plasma ferritin concentration in adults with obesity, suggesting that skeletal muscle may be an underappreciated iron store.

Acute Aerobic Exercise Remodels the Adipose Tissue Progenitor Cell Phenotype in Obese Adults.

Adipose tissue pathology in obese patients often features impaired adipogenesis, angiogenesis, and chronic low-grade inflammation, all of which are regulated in large part by adipose tissue stromal vascular cells [SVC; i.e., non-adipocyte cells within adipose tissue including preadipocytes, endothelial cells (ECs), and immune cells]. Exercise is known to increase subcutaneous adipose tissue lipolysis, but the impact of exercise on SVCs in adipose tissue has not been explored. The purpose of this study was to assess the effects of a session of exercise on preadipocyte, EC, macrophage, and T cell content in human subcutaneous adipose tissue. We collected abdominal subcutaneous adipose tissue samples from 10 obese adults (BMI 33 ± 3 kg/m2, body fat 41 ± 7%) 12 h after a 60 min acute session of endurance exercise (80 ± 3%HRpeak) vs. no acute exercise session. SVCs were isolated by collagenase digestion and stained for flow cytometry. We found that acute exercise reduced preadipocyte content (38 ± 7 vs. 30 ± 13%SVC; p = 0.04). The reduction was driven by a decrease in CD34hi preadipocytes (18 ± 5 vs. 13 ± 6%SVC; p = 0.002), a subset of preadipocytes that generates high lipolytic rate adipocytes ex vivo. Acute exercise did not alter EC content. Acute exercise also did not change total immune cell, macrophage, or T cell content, and future work should assess the effects of exercise on subpopulations of these cells. We conclude that exercise may rapidly regulate the subcutaneous adipose tissue preadipocyte pool in ways that may help attenuate the high lipolytic rates that are commonly found in obesity.

Moderate-Intensity Exercise and High-Intensity Interval Training Affect Insulin Sensitivity Similarly in Obese Adults.

OBJECTIVE: We compared the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on insulin sensitivity and other important metabolic adaptations in adults with obesity. METHODS: Thirty-one inactive adults with obesity (age: 31 ±â€…6 years; body mass index: 33 ±â€…3 kg/m2) completed 12 weeks (4 sessions/week) of either HIIT (10 × 1-minute at 90%HRmax, 1-minute active recovery; n = 16) or MICT (45 minutes at 70%HRmax; n = 15). To assess the direct effects of exercise independent of weight/fat loss, participants were required to maintain body mass. RESULTS: Training increased peak oxygen uptake by ~10% in both HIIT and MICT (P < 0.0001), and body weight/fat mass were unchanged. Peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) was ~20% greater the day after the final exercise session compared to pretraining (P < 0.01), with no difference between HIIT and MICT. When trained participants abstained from exercise for 4 days, insulin sensitivity returned to pretraining levels in both groups. HIIT and MICT also induced similar increases in abundance of many skeletal muscle proteins involved in mitochondrial respiration and lipid and carbohydrate metabolism. Training-induced alterations in muscle lipid profile were also similar between groups. CONCLUSION: Despite large differences in training intensity and exercise time, 12 weeks of HIIT and MICT induce similar acute improvements in peripheral insulin sensitivity the day after exercise, and similar longer term metabolic adaptations in skeletal muscle in adults with obesity. These findings support the notion that the insulin-sensitizing effects of both HIIT and MICT are mediated by factors stemming from the most recent exercise session(s) rather than adaptations that accrue with training.

Energy Deficit Required for Exercise-induced Improvements in Glycemia the Next Day.

PURPOSE: This study determined the impact of an exercise-induced energy deficit on postprandial and 24 h glycemic control the day after a session of exercise. METHODS: Fifteen healthy participants (m/f = 5/10, 27 ± 6 yr, body mass index = 24 ± 3 kg·m, peak oxygen consumption [V˙O2peak] = 36 ± 9 mL·kg·min) completed two separate 5-d experimental trials performed under "free-living" conditions. On day 1 of each trial, participants were fitted with a continuous glucose monitor and abstained from exercise. Day 2 served as a nonexercise control (NoEx). On day 3, participants exercised at 3:00 PM (65% V˙O2peak) until they expended 350 kcals (~45 min). The diet during both experimental trials was identical with the exception of meals after this exercise session. During one trial, the dinner after exercise did not replenish the 350 kcal expended during exercise, thereby establishing an exercise energy deficit (ExDEF). During the other experimental trial, the dinner after exercise contained an additional 350 kcal to compensate for the energy expended during exercise, and thereby maintained energy balance after exercise (ExBAL). Free-living glycemia was measured the day before exercise (NoEx) and the day after exercise under ExDEF and ExBAL conditions. RESULTS: The day after exercise, 3 h postprandial area under the curve was lower after breakfast in ExDEF compared with ExBAL (16.0 ± 1.8 vs 17.0 ± 1.6 mmol·L·h per 3 h, P = 0.01), but did not differ between groups after lunch (P = 0.24), dinner (P = 0.39), or evening snack (P = 0.45). Despite differences in the glycemic response to breakfast, 24 h glycemia did not differ between ExDEF and ExBAL (area under the curve = 128 ± 10 vs 131 ± 10 mmol·L·h per 24 h, respectively; P = 0.54). CONCLUSIONS: An exercise-induced energy deficit lowered the glycemic response to breakfast the next day-but this energy deficit did not impact total 24 h glycemia, the day after exercise in metabolically healthy adults.

Weight Loss Improves ß-Cell Function in People With Severe Obesity and Impaired Fasting Glucose: A Window of Opportunity.

BACKGROUND: In people with obesity, ß-cell function may adapt to insulin resistance. We describe ß-cell function in people with severe obesity and normal fasting glucose (NFG), impaired fasting glucose (IFG), and type 2 diabetes (T2DM), as assessed before, 3 to 6 months after, and 2 years after medical weight loss to describe its effects on insulin sensitivity, insulin secretion, and ß-cell function. METHODS: Fifty-eight participants with body mass index (BMI) ≥ 35 kg/m2 (14 with NFG, 24 with IFG, and 20 with T2DM) and 13 normal weight participants with NFG underwent mixed meal tolerance tests to estimate insulin sensitivity (S[I]), insulin secretion (Φ), and ß-cell function assessed as model-based Φ adjusted for S(I). All 58 obese participants were restudied at 3 to 6 months and 27 were restudied at 2 years. RESULTS: At 3 to 6 months, after a 20-kg weight loss and a decrease in BMI of 6 kg/m2, S(I) improved in all obese participants, Φ decreased in obese participants with NFG and IFG and tended to decrease in obese participants with T2DM, and ß-cell function improved in obese participants with NFG and tended to improve in obese participants with IFG. At 2 years, ß-cell function deteriorated in participants with NFG and T2DM but remained significantly better in participants with IFG compared to baseline. CONCLUSIONS: Short-term weight loss improves ß-cell function in participants with NFG and IFG, but ß-cell function tends to deteriorate over 2 years. In participants with IFG, weight loss improves longer-term ß-cell function relative to baseline and likely relative to no intervention, suggesting that obese people with IFG are a subpopulation whose ß-cell function is most likely to benefit from weight loss.

Plasma ferritin concentration is positively associated with in vivo fatty acid mobilization and insulin resistance in obese women.

NEW FINDINGS: What is the central question of this study? Do obese women with relatively high whole-body iron stores exhibit elevated in vivo rates of fatty acid (FA) release from adipose tissue compared with a well-matched cohort of obese women with relatively low iron stores? What is the main finding and its importance? Obese women with high plasma [ferritin] (a marker of whole-body iron stores) had greater FA mobilization, lipolytic activation in adipose tissue and insulin resistance (IR) compared with obese women with lower plasma [ferritin]. Given that elevated FA mobilization is intimately linked with the development of IR, these findings suggest that elevated iron stores might contribute to IR in obesity by increasing systemic FA availability. ABSTRACT: High rates of fatty acid (FA) mobilization from adipose tissue are associated with insulin resistance (IR) in obesity. In vitro evidence suggests that iron stimulates lipolysis in adipocytes, but whether iron is related to in vivo FA mobilization is unknown. We hypothesized that plasma ferritin concentration ([ferritin]), a marker of body iron stores, would be positively associated with FA mobilization. We measured [ferritin], the rate of appearance of FA in the systemic circulation (FA Ra; stable isotope dilution), key adipose tissue lipolytic proteins and IR (hyperinsulinaemic-euglycaemic clamp) in 20 obese, premenopausal women. [Ferritin] was correlated with FA Ra (r = 0.65; P = 0.002) and IR (r = 0.57; P = 0.008); these relationships remained significant after controlling for body mass index and plasma [C-reactive protein] (a marker of systemic inflammation) in multiple regression analyses. We then stratified subjects into tertiles based on [ferritin] to compare subjects with 'High-ferritin' versus 'Low-ferritin'. Plasma [hepcidin] was more than fivefold greater (P < 0.05) in the High-ferritin versus Low-ferritin group, but there was no difference in plasma [C-reactive protein] between groups, indicating that the large difference in plasma [ferritin] reflects a difference in iron stores, not systemic inflammation. We found that FA Ra, adipose protein abundance of hormone-sensitive lipase and adipose triglyceride lipase, and IR were significantly greater in subjects with High-ferritin versus Low-ferritin (all P < 0.05). These data provide the first evidence linking iron and in vivo FA mobilization and suggest that elevated iron stores might contribute to IR in obesity by increasing systemic FA availability.

"Fat Shadows" From DXA for the Qualitative Assessment of Lipodystrophy: When a Picture Is Worth a Thousand Numbers.

OBJECTIVE: Lipodystrophy syndromes are a heterogeneous group of disorders associated with selective absence of fat. Currently, the diagnosis is established only clinically. RESEARCH DESIGN AND METHODS: We developed a new method from DXA scans called a "fat shadow," which is a color-coded representation highlighting only the fat tissue. We conducted a blinded retrospective validation study to assess its usefulness for the diagnosis of lipodystrophy syndromes. RESULTS: We evaluated the fat shadows from 16 patients (11 female and 5 male) with generalized lipodystrophy (GL), 57 (50 female and 7 male) with familial partial lipodystrophy (FPLD), 2 (1 female and 1 male) with acquired partial lipodystrophy, and 126 (90 female and 36 male) control subjects. FPLD was differentiated from control subjects with 85% sensitivity and 96% specificity (95% CIs 72-93 and 91-99, respectively). GL was differentiated from nonobese control subjects with 100% sensitivity and specificity (95% CIs 79-100 and 92-100, respectively). CONCLUSIONS: Fat shadows provided sufficient qualitative information to infer clinical phenotype and differentiate these patients from appropriate control subjects. We propose that this method could be used to support the diagnosis.

Changes in markers for cardio-metabolic disease risk after only 1-2 weeks of a high saturated fat diet in overweight adults.

PURPOSE: Diets high in saturated fat acids (SFA) have been linked with cardio-metabolic disease risk. The purpose of this study was to determine whether only 1-2 weeks of a high SFA diet could impact disease risk factors in overweight adults who normally eat a relatively low proportion of SFA (i.e., <40% of dietary fat). METHODS: Twelve overweight (BMI: 27±1 kg/m2) young adults were studied before and after a 2-week diet that increased the proportion of SFA (<40% to 60% of dietary fat), while maintaining their daily intake of total fat, carbohydrate, protein, and calories. Insulin resistance, blood pressure, plasma markers of liver damage, total plasma cholesterol concentrations, and fatty acid profile within plasma and skeletal muscle lipid pools were assessed before and after the intervention. RESULTS: Total plasma cholesterol concentration increased (148±5 vs. 164±8 mg/dl; P<0.05) after only one week, due exclusively to an increase in LDL-cholesterol (78±4 vs. 95±7 mg/dl; P<0.05). After two weeks, plasma aspartate amino transferase (AST) concentration increased (P<0.05) but we found no change in insulin resistance, or resting blood pressure. The diet increase the proportion of SFA in plasma (35±1% vs. 39±2%; P<0.05) and the intramyocellular triglyceride pool (32±1% vs. 37±1%; P<0.05) suggesting the fatty acids in these pools may readily exchange. CONCLUSIONS: Although blood lipids remain within normal clinical range, increasing saturated fat in diet for only 2 weeks raises plasma markers of cardiovascular risk (LDL-cholesterol) and liver damage (AST). In overweight, but healthy-young adults SFA accumulate in plasma and muscle after only 1-2 weeks of dietary increase.

Acute endurance exercise increases Vegfa mRNA expression in adipose tissue of rats during the early stages of weight gain.

The aim of this study was to determine the effects of acute exercise on key factors regulating angiogenesis in adipose tissue. Adipose tissue Vegf-a messenger RNA expression was upregulated immediately after acute exercise (p < 0.05) in rats consuming a high-fat diet, but was lower after exercise (p < 0.05) in rats consuming a low-fat diet. Our working hypothesis is that acute exercise augments angiogenic signaling under conditions when adipose tissue is expanding, and with repeated exercise sessions these signals can accrue to enhance vascularization.

Expression of macrophage genes within skeletal muscle correlates inversely with adiposity and insulin resistance in humans.

Local inflammation in obese adipose tissue has been shown to contribute to insulin resistance; however, the role of macrophage infiltration within skeletal muscle is still debatable. This study aimed to evaluate the association of skeletal muscle macrophage gene expression with adiposity levels and insulin sensitivity in obese patients. Twenty-two nondiabetic obese patients and 23 healthy lean controls were included. Obese patients underwent a 3-month weight loss intervention. Macrophage gene expression in skeletal muscle (quantitative real-time polymerase chain reaction), body composition (dual-energy X-ray absorptiometry), and insulin sensitivity (homeostatic model assessment (HOMA) and oral glucose tolerance test) were compared between groups and their associations were analyzed. To validate skeletal muscle findings, we repeated the analyses with macrophage gene expression in adipose tissue. Expression levels of macrophage genes (CD68, CD11b, CD206, CD16, CD40, and CD163) were lower in skeletal muscle tissue of obese versus lean participants. Macrophage gene expression was also found to be inversely associated with adiposity, fasting insulin, and HOMA (r = -0.4 ∼ -0.6, p < 0.05), as well as positively associated with insulin sensitivity (r = 0.4 ∼ 0.8, p < 0.05). On the other hand, adipose tissue macrophage gene expression showed higher levels in obese versus lean participants, presenting a positive association with adiposity levels. Macrophage gene expression, in both skeletal and adipose tissue samples, was only minimally affected by the weight loss intervention. In contrast with the established positive relationship between adiposity and macrophage gene expression, an unexpected inverse correlation between these 2 variables was observed in skeletal muscle tissue. Additionally, muscle macrophage gene expression was inversely correlated with insulin resistance.

Aerobic exercise elevates markers of angiogenesis and macrophage IL-6 gene expression in the subcutaneous adipose tissue of overweight-to-obese adults.

Alterations in the inflammatory state, metabolic function, and structure of subcutaneous adipose tissue (SAT) can impact the development of insulin resistance in obesity. Exercise can improve metabolic health in obesity, but the effects of exercise on SAT are not well known. The purpose of this study was to examine the effects of acute exercise and habitual exercise training on mRNA expression of markers of lipid metabolism, inflammation, fibrosis, and hypoxia/angiogenesis in SAT, as well as adipocyte cell size. We recruited overweight-to-obese adults who exercised regularly (ACTIVE: n = 8) or were sedentary (SED: n = 12). The groups were well matched for age (27 ± 1 vs. 24 ± 2 yr), body mass index (29 ± 1 vs. 27 ± 1 kg/m2), and body composition (30 ± 1 vs. 29 ± 1% body fat), but as expected, cardiorespiratory fitness was greater in ACTIVE vs. SED (V̇o2peak: 51 ± 3 vs. 42 ± 1 ml·kg fat-free mass-1·min-1; P = 0.01). Abdominal SAT biopsy samples were obtained before and 1 h after a single session of aerobic exercise (60 min at ~65% V̇o2peak). The exercise session increased SAT mRNA expression of VEGFA, an important regulator of angiogenic processes, in both groups. In addition, SAT from ACTIVE subjects had greater mRNA expression of the endothelial cell marker CD31 compared with SED, which may be a cumulative effect of the transient increases in VEGFA with regular exercise. We also magnetically sorted CD14+ immune cells from SAT samples and found that IL-6 expression was elevated in ACTIVE compared with SED. In conclusion, exercise initiates increases in factors related to angiogenic processes and may promote alterations in macrophage inflammation in SAT.NEW & NOTEWORTHY Acute exercise in overweight/obese adults increased subcutaneous adipose tissue (SAT) mRNA expression of VEGFA, an important regulator of angiogenesis and capillary growth. In addition, subjects that regularly exercise had elevated SAT CD31 mRNA expression and elevated IL-6 mRNA in adipose tissue macrophages compared with nonexercisers. This study demonstrates that aerobic exercise may alter processes related to whole body metabolic outcomes in obesity, such as angiogenesis and immune response, in the SAT of overweight/obese adults.

Factors regulating subcutaneous adipose tissue storage, fibrosis, and inflammation may underlie low fatty acid mobilization in insulin-sensitive obese adults.

Although the rate of fatty acid release from adipose tissue into the systemic circulation is very high in most obese adults, some obese adults maintain relatively low rates of fatty acid release, which helps protect them against the development of systemic insulin resistance. The primary aim of this study was to identify factors in adipose tissue that may underlie low vs. high rates of fatty acid mobilization in a relatively homogeneous cohort of obese adults. We measured systemic fatty acid rate of appearance (FA Ra) via 13C-palmitate isotope dilution, and we obtained subcutaneous abdominal adipose tissue samples from 30 obese adults (BMI: 38 ± 1 kg/m2, age: 30 ± 2 yr) after an overnight fast. We then measured insulin sensitivity using a hyperinsulinemic-euglycemic clamp. Confirming our previous work, insulin sensitivity was inversely proportional to FA Ra (R2 = 0.50; P < 0.001). Immunoblot analysis of subcutaneous adipose tissue samples revealed that, compared with obese adults with high FA Ra, those with low FA Ra had lower markers of lipase activation and higher abundance of glycerol-3-phosphate acyltransferase, which is a primary enzyme for fatty acid esterification. Microarray and pathway analysis provided evidence of lower fibrosis and lower SAPK/JNK pathway activation in obese adults with low FA Ra compared with those with high FA Ra. Our findings suggest that alterations in factors regulating triglyceride storage in adipose tissue, along with lower fibrosis and inflammatory pathway activation, may underlie maintenance of a relatively low FA Ra in obesity, which may help protect against the development of insulin resistance.

Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes.

Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKɛ and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKɛ and TBK1, in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that dual-specificity inhibitors of IKKɛ and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients.