Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D

Physiological and Psychological Effects of Deception on Pacing Strategy and Performance: A Review

The aim of an optimal pacing strategy during exercise is to enhance performance whilst ensuring physiological limits are not surpassed, which has been shown to result in a metabolic reserve at the end of the exercise. There has been debate surrounding the theoretical models that have been proposed to explain how pace is regulated, with more recent research investigating a central control of exercise regulation. Deception has recently emerged as a common, practical approach to manipulate key variables during exercise. There are a number of ways in which deception interventions have been designed, each intending to gain particular insights into pacing behaviour and performance. Deception methodologies can be conceptualised according to a number of dimensions such as deception timing (prior to or during exercise), presentation frequency (blind, discontinuous or continuous) and type of deception (performance, biofeedback or environmental feedback). However, research evidence on the effects of deception has been perplexing and the use of complex designs and varied methodologies makes it difficult to draw any definitive conclusions about how pacing strategy and performance are affected by deception. This review examines existing research in the area of deception and pacing strategies, and provides a critical appraisal of the different methodological approaches used to date. It is hoped that this analysis will inform the direction and methodology of future investigations in this area by addressing the mechanisms through which deception impacts upon performance and by elucidating the potential application of deception techniques in training and competitive settings

The role of sense of effort on self-selected cycling power output

PURPOSE: We explored the effects of the sense of effort and accompanying perceptions of peripheral discomfort on self-selected cycle power output under two different inspired O2 fractions. METHODS: On separate days, eight trained males cycled for 5 min at a constant subjective effort (sense of effort of '3' on a modified Borg CR10 scale), immediately followed by five 4-s progressive submaximal (sense of effort of "4, 5, 6, 7, and 8"; 40 s between bouts) and two 4-s maximal (sense of effort of "10"; 3 min between bouts) bouts under normoxia (NM: fraction of inspired O2 [FiO2] 0.21) and hypoxia (HY: [FiO2] 0.13). Physiological (Heart Rate, arterial oxygen saturation (SpO2) and quadriceps Root Mean Square (RMS) electromyographical activity) and perceptual responses (overall peripheral discomfort, difficulty breathing and limb discomfort) were recorded. RESULTS: Power output and normalized quadriceps RMS activity were not different between conditions during any exercise bout (p > 0.05) and remained unchanged across time during the constant-effort cycling. SpO2 was lower, while heart rate and ratings of perceived difficulty breathing were higher under HY, compared to NM, at all time points (p < 0.05). During the constant-effort cycling, heart rate, overall perceived discomfort, difficulty breathing and limb discomfort increased with time (all p < 0.05). All variables (except SpO2) increased along with sense of effort during the brief progressive cycling bouts (all p < 0.05). During the two maximal cycling bouts, ratings of overall peripheral discomfort displayed an interaction between time and condition with ratings higher in the second bout under HY vs. NM conditions. CONCLUSION: During self-selected, constant-effort and brief progressive, sub-maximal, and maximal cycling bouts, mechanical work is regulated in parallel to the sense of effort, independently from peripheral sensations of discomfort

Adipocyte mesenchymal transition contributes to mammary tumor progression

Obesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment. Single-cell sequencing reveals that these de-differentiated adipocytes lose their original identities and transform into multiple cell types, including myofibroblast- and macrophage-like cells, with their characteristic features involved in immune response, inflammation, and extracellular matrix remodeling. The de-differentiated cells are metabolically distinct from tumor-associated fibroblasts but exhibit comparable effects on tumor cell proliferation. Inducing de-differentiation by Xbp1s overexpression promotes tumor progression despite lower adiposity. In contrast, promoting lipid-storage capacity in adipocytes through MitoNEET overexpression curbs tumor growth despite greater adiposity. Collectively, the metabolic interplay between tumor cells and adipocytes induces adipocyte mesenchymal transition and contributes to reconfigure the stroma into a more tumor-friendly microenvironment

Endurance performance is influenced by perceptions of pain and temperature: Theory, applications and safety considerations.

Models of endurance performance now recognise input from the brain, including an athlete’s ability to cope with various non-pleasurable perceptions during exercise, such as pain and temperature. Exercise training can reduce perceptions of both pain and temperature over time, partly explaining why athletes generally have a higher pain tolerance, despite a similar pain threshold, compared with active controls. Several strategies with varying efficacy may ameliorate the perceptions of pain (e.g. acetaminophen, transcranial direct current stimulation and transcutaneous electrical stimulation) and temperature (e.g. menthol beverages, topical menthol products and other cooling strategies, especially those targeting the head) during exercise to improve athletic performance. This review describes both the theory and practical applications of these interventions in the endurance sport setting, as well as the potentially harmful health consequences of their use

The challenges of interrogating adipose tissue extracellular vesicle functions in physiology

Adipose tissue-derived extracellular vesicles (EVs) are at the center of the budding field of EV signaling in metabolic regulation for their strong regulatory effects on local and systemic metabolism. This essay will highlight seminal studies in adipose tissue EV research, critically assess current adipose tissue EV research strategies and discuss the obstacles the field faces moving forward

Rapid inhibition of pyruvate dehydrogenase: an initiating event in high dietary fat-induced loss of metabolic flexibility in the heart.

Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on fatty acids for energy production

Pyruvate Dehydrogenase Activity is Diminished and Phosphorylation Enhanced in Respiring Cardiac Mitochondria from Mice Fed High Dietary Fat.

<p>Cardiac mitochondria (0.25 mg/mL) were incubated with 100 µM pyruvate and 1.0 mM malate. At 2.0 min, state 3 respiration was initiated by the addition of 0.25 mM ADP. <b>A</b>. PDH activity at 1.5 min, during state 2 respiration, and at 4.5 min, during state 3 respiration, in cardiac mitochondria from mice fed control or high fat diet for 1 d (n = 5). <b>B</b>. PDH activity at 4.5 min, during state 3 respiration, for cardiac mitochondria from mice fed a control or high fat diet for indicated times. Data are presented as the % decrease relative to controls (n = 5, 6, and 6 for 1 d, 1 wk, and 20 wk). <b>C</b>. Mitochondria were incubated with 100 µM or 10 mM pyruvate and 1.0 mM malate in the presence or absence of 25 µM palmitoylcarnitine. At 2.0 min, ADP was added (0.25 mM) to initiate state 3 respiration and PDH activity was assayed at 4.5 min (n = 5). <b>D</b>. Western blot analysis (representative of n = 5) of phosphorylation status for each site on the PDH E1α subunit during state 2 and 3 respiration in cardiac mitochondria isolated from mice on indicated diets for 1 d. E. Relative phosphorylation status during state 3 respiration in cardiac mitochondria isolated from mice fed a control (arbitrary unit 1) versus high fat diet for 1 d quantified by densitometric analysis of the Western blots (n = 5). All data are presented as the mean ± SEM with <i>p</i> values: * < 0.05; ** < 0.01; and *** < 0.001.</p

High Dietary Fat Drives a Selective Increase in the Expression of PDK4 in the Heart.

<p>mRNA and protein content of PDK and PDP isoforms were measured in hearts of mice fed either the control or high fat diet for 1 d or 1 wk. <b>A</b>. mRNA expression determined by qRT-PCR (n = 5 and 9 for 1 d and 1 wk). <b>B</b>. Protein content measured by quantitative mass spectrometry (n = 5 and 6 for 1 d and 1 wk). <b>C</b>. Expression of PDK4 in isolated cardiac mitochondria quantified by densitometric analysis of Western blots (n = 5 for 1 wk). All data are presented as the mean ± SEM with <i>p</i> values: ** < 0.01; and *** < 0.001.</p