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Brown adipose tissue (BAT), brown-in-white (“brite”) and “beige” adipocytes share the unique ability of converting chemical energy into heat and play a critical role in the adaptive thermogenesis response promoting nonshivering thermogenesis. Uncoupling Protein-1 (UCP1), which allows the uncoupling of substrate oxidation from phosphorylation of ADP, represents the molecular signature of BAT and beige adipocytes. Until recently, the physiologic role of BAT and beige adipocytes depots was thought to be limited to small mammalians and newborns.

The discovery of BAT in adult humans and the demonstration of the presence of inducible BAT activity in white adipose tissue by beige adipocytes have generated enthusiasm as potential targets for treatment of obesity and other disorders due to sustained positive energy balance. These findings are particularly important since in vitro studies have demonstrated that preadipocytes can be directed toward a common brown phenotype by multiple pathways that, in turn, may be exploited for therapeutic interventions. In adult humans, BAT activity is more evident in deep neck fat depots and, to a lesser degree, in subcutaneous adipose tissue, with a transcriptome signature resembling the rodent beige fat. This observation supports the hypothesis that human BAT activity and capacity can be modulated. To this end, we have directed our translational research program toward the characterization of beige fat in humans and on the effects of hormonal and environmental drivers in the adaptive thermogenesis response. Mild cold exposure, within the temperature range commonly employed in climate-controlled buildings, is sufficient to generate a significant increase in non-shivering thermogenesis driven by BAT and beige adipocyte activation. In turn, adaptive thermogenesis generates a specific hormonal signature and promotes glucose disposal. Chronic exposure to mild cold induces expansion of BAT mass and activity, whereas exposure to warm climate abrogates them. Additionally, the metabolic effects of BAT mass expansion are evident only upon stimulation of BAT activity, indicating that both expansion and activation of BAT are necessary and complementary strategies to pursue. From an experimental standpoint, human preadipocytes represent a viable experimental platform to mechanistically interrogate different pathways that are able to expand and activate browning. Our laboratory has focused on studying FGF-21, and FNDC5/irisin in their capacity to promote the browning process. Compared to a white differentiation medium, the addition of either FGF-21 or FNDC5 results in a reprogramming toward a brown phenotype, as indicated by the display of brown transcriptome signature and, functionally, by the increase in oxygen consumption following catecholamine treatment, indicating an increase in substrate utilization. Collectively, the integration of a detailed assessment of human physiology with mechanistic observations in cell culture systems can provide a unique opportunity to translate observations from experimental models to actionable therapeutic targets.

To sustain metabolism, intracellular ATP concentration must be regulated within an appropriate range. This coordination is achieved through the function of the AMP-activated protein kinase (AMPK), a cellular “fuel gauge” that is expressed in essentially all eukaryotic cells as heterotrimeric complexes containing catalytic α subunits and regulatory β and γ subunits. When cellular energy status has been compromised, AMPK is activated by increases in AMP:ATP or ADP:ATP ratios and acts to restore energy homeostasis by stimulating energy production via catabolic pathways while decreasing non-essential energy-consuming pathways. Although the primary function of AMPK is to regulate energy homeostasis at a cell-autonomous level, in multicellular organisms, the AMPK system has evolved to interact with hormones to regulate energy intake and expenditure at the whole body level. Thus, AMPK functions as a signaling hub, coordinating anabolic and catabolic pathways to balance nutrient supply with energy demand at both the cellular and whole-body levels. AMPK is activated by various metabolic stresses such as ischemia or hypoxia or glucose deprivation and has both acute and long-term effects on metabolic pathways and key cellular functions. In addition, AMPK appears to be a major sensor of energy demand in exercising muscle and acts both as a multitask gatekeeper and an energy regulator in skeletal muscle. Acute activation of AMPK has been shown to promote glucose transport and fatty acid oxidation while suppressing glycogen synthase activity and protein synthesis. Chronic activation of AMPK induces a shift in muscle fiber type composition, reduces markers of muscle degeneration and enhances muscle oxidative capacity potentially by stimulating mitochondrial biogenesis. Furthermore, recent evidence demonstrates that AMPK may not only regulate metabolism during exercise but also in the recovery phase. AMPK acts as a molecular transducer between exercise and insulin signaling and is necessary for the ability of prior contraction/exercise to increase muscle insulin sensitivity. Based on these observations, drugs that activate AMPK might be expected to be useful in the treatment of metabolic disorders and insulin resistance in various conditions.

The aim of this report is to evaluate the relationships between baseline levels of adrenal, gonadal and conjugated steroids and baseline cardiorespiratory fitness, as assessed by maximal oxygen uptake (VOmax), as well as its response to a standardized exercise program. To address this aim we used a subset of the HERITAGE Family Study (N = 448). In men, significant positive associations were found between baseline VOmax/kg weight and plasma levels of androsterone glucuronide (ADTG), dihydrotesterone (DHT), 17 hydroxy progesterone (OHPROG), sex hormone binding globulin (SHBG), and testosterone (TESTO), and negative association with aldosterone (ALDO). In women, only the free androgen index (FAI) was negatively associated with baseline VOmax/kg weight. Neither baseline plasma steroid levels nor SHBG concentrations were associated with the gains in VOmax resulting from exposure to the 20-week aerobic exercise program after adjustment for baseline values, age and ethnicity (white or black). We conclude that baseline plasma steroid levels are only weakly associated with individual differences in cardiorespiratory fitness in the sedentary state in men but not in women, whereas no association could be detected with trainability, as defined by the change in VOmax with the exercise program.

Exercise training-induced adaptations in human skeletal muscle are largely determined by the mode, volume, intensity and frequency of the training stimulus. However, a growing body of evidence demonstrates that the availability of endogenous and exogenous macronutrients can modify multiple intramuscular responses to both endurance- and resistance-based exercise. Acutely manipulating substrate availability (by altering diet composition and/or timing of meals) rapidly alters the concentration of blood-borne substrates and hormones that modulate several receptor-mediated signaling pathways. The release of cytokines and growth factors from contracting skeletal muscle also stimulates cell surface receptors and activates many intracellular signaling cascades. These local and systemic factors cause marked perturbations in the storage profile of skeletal muscle (and other insulin-sensitive tissues) that, in turn, exert pronounced effects on resting fuel metabolism and patterns of fuel utilization during exercise. When repeated over weeks and months, such nutrient-exercise interactions have the potential to alter numerous adaptive processes in skeletal muscle that ultimately drive the phenotype-specific variability observed between individuals. One strategy that augments endurance-training adaptation is commencing exercise with low muscle glycogen concentration (“train-low”). The amplified training response observed with low endogenous carbohydrate availability is likely regulated by enhanced activation of key cell signalling kinases (e.g., AMPK, p38MAPK), transcription factors (e.g., p53, PPARδ) and transcriptional co-activators (e.g., PGC-1α), such that a coordinated up-regulation of both the nuclear and mitochondrial genomes occurs. This chapter provides a contemporary perspective of our understanding of the molecular and cellular events that take place in skeletal muscle in response to exercise commenced after alterations in nutrient availability and discusses how the ensuing hormonal milieu interacts with specific contractile stimulus to modulate many of the acute responses to exercise, thereby potentially promoting or inhibiting subsequent training adaptation.

Recurring contraction-relaxation cycles exert a massive mechanical load on muscle fibers. Training adaptation therefore entails the promotion of a series of biological programs aimed at inducing a better stress response but also at optimizing repair processes. Muscle regeneration is controlled by an intricate, tightly coordinated engagement of muscle fibers, satellite cells, macrophages and other cell types. In this review, we discuss some of the recent insights into the regulation of muscle repair and regeneration in exercised muscle, elucidate the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in this context, and speculate about potential implications for the treatment of muscle diseases.

MicroRNAs (miRNA) are a noncoding RNA species that play important roles in the regulation of gene expression. Since miRNAs are able to target multiple genes simultaneously, miRNAs provide a mechanism for efficiently modulating a whole pathway to change or alter the functional properties in a particular target tissue. Ablation of miRNA processing specifically in skeletal muscle results in muscle abnormalities and perinatal death, underscoring that miRNAs control essential processes in skeletal muscle development and function. In this chapter we summarise current knowledge on miRNAs involved in skeletal muscle differentiation, disease and exercise.

In our efforts to identify molecular mediators of the benefits of exercise to human health, we have uncovered a biochemical pathway in skeletal muscle that positively impacts mental health. This mechanism is activated by endurance training and controlled by the transcriptional coactivator PGC-1α1, which induces transcription of several kynurenine aminotransferase (KAT) genes in muscle. KAT enzymes catabolize the neuroinflammatory tryptophan metabolite kynurenine, which can accumulate in the brain and lead to alterations associated with stress-induced depression (among other psychiatric diseases). Here, we discuss our findings in the context of what is known about the kynurenine pathway of tryptophan degradation and how its many metabolites can directly affect the brain. These findings provide a mechanism for how physical exercise can improve mental health and offers potential therapeutic targets for future antidepressant medications.

Exercise can improve cognitive function and the outcome of neurodegenerative diseases like Alzheimer’s disease. This effect has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Recently, we have reported a PGC-1α-FNDC5/irisin pathway that is activated by exercise in the hippocampus in mice and induces a neuroprotective gene program, including . This review will focus on FNDC5 and its secreted form “irisin,” a newly discovered myokine, its role in the nervous system and its therapeutic potential. In addition, we will briefly discuss the role of other exercise-induced myokines in positive brain effects.