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Simple Summary: Exercise has well-known health benefits, but the way our muscles use carbohydrates and lipids as fuel during exercise is complex. It is not just about the physical activity itself; it also depends on our body's metabolic state. The balance between using carbs and fats affects exercise performance. This review aims to provide a comprehensive look at how our bodies choose fuel sources during exercise by summarizing existing research. Understanding this can lead to advancements in exercise science and personalized exercise strategies for better health and performance. Exercise is widely recognized for its positive impact on human health and well-being. The process of utilizing substrates in skeletal muscle during exercise is intricate and governed by complex mechanisms. Carbohydrates and lipids serve as the primary fuel sources for skeletal muscle during exercise. It is now understood that fuel selection during exercise is not solely determined by physical activity itself but is also influenced by the overall metabolic state of the body. The balance between lipid and carbohydrate utilization significantly affects exercise capacity, including endurance, fatigue, and overall performance. Therefore, comprehensively understanding the regulation of substrate utilization during exercise is of utmost importance. The aim of this review is to provide an extensive overview of the current knowledge regarding the pathways involved in the regulation of substrate utilization during exercise. By synthesizing existing research, we can gain a holistic perspective on the intricate relationship between exercise, metabolism, and fuel selection. This advanced understanding has the potential to drive advancements in the field of exercise science and contribute to the development of personalized exercise strategies for individuals looking to optimize their performance and overall health. [ABSTRACT FROM AUTHOR]

The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat-fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis., Introduction One of the major concepts emerging from the last 2 decades of metabolism research is the notion of 'metainflammation,' the state of chronic low-grade inflammation that develops during periods [...]

Skeletal muscle is a major regulator of glycemic control at rest, and glucose utilization increases drastically during exercise. Sustaining a high glucose utilization via glycolysis requires efficient replenishment of NAD+ in the cytosol. Apoptosis-inducing mitochondrion-associated factor 2 (AIFM2) was previously shown to be a NADH oxidoreductase domain-containing flavoprotein that promotes glycolysis for diet and cold-induced thermogenesis. Here, we find that AIFM2 is selectively and highly induced in glycolytic extensor digitorum longus (EDL) muscle during exercise. Overexpression (OE) of AIFM2 in myotubes is sufficient to elevate the NAD+-to-NADH ratio, increasing the glycolytic rate. Thus, OE of AIFM2 in skeletal muscle greatly increases exercise capacity, with increased glucose utilization. Conversely, muscle-specific Aifm2 depletion via in vivo transfection of hairpins against Aifm2 or tamoxifen-inducible haploinsufficiency of Aifm2 in muscles decreases exercise capacity and glucose utilization in mice. Moreover, muscle-specific introduction of NDE1, Saccharomyces cerevisiae external NADH dehydrogenase (NDE), ameliorates impairment in glucose utilization and exercise intolerance of the muscle-specific Aifm2 haploinsufficient mice. Together, we show a novel role for AIFM2 as a critical metabolic regulator for efficient utilization of glucose in glycolytic EDL muscles. [ABSTRACT FROM AUTHOR]

Chronic low-grade inflammation, often referred to as metainflammation, develops in response to overnutrition and is a major player in the regulation of insulin sensitivity. While many studies have investigated adipose tissue inflammation from the perspective of the immune cell compartment, little is known about how adipocytes intrinsically contribute to metainflammation and insulin resistance at the molecular level. In this study, we demonstrate a novel role for Jumonji C domain-containing protein 8 (JMJD8) as an adipocyte-intrinsic molecular nexus between inflammation and insulin resistance. We determined that JMJD8 was highly enriched in white adipose tissue, especially in the adipocyte fraction. Adipose JMJD8 levels were dramatically increased in obesity-associated insulin resistance models. Its levels were increased by feeding and insulin and inhibited by fasting. A JMJD8 gain-of-function was sufficient to drive insulin resistance, whereas loss-of-function improved insulin sensitivity in mouse and human adipocytes. Consistent with this, Jmjd8-ablated mice had increased whole-body and adipose insulin sensitivity and glucose tolerance on both chow and a high-fat diet, while adipocyte-specific Jmjd8-overexpressing mice displayed worsened whole-body metabolism on a high-fat diet. We found that JMJD8 affected the transcriptional regulation of inflammatory genes. In particular, it was required for lipopolysaccharide-mediated inflammation and insulin resistance in adipocytes. For this, JMJD8 required interferon regulatory factor 3 to mediate its actions in adipocytes. Together, our results demonstrate that JMJD8 acts as a novel molecular factor that drives adipocyte inflammation in conjunction with insulin sensitivity. [ABSTRACT FROM AUTHOR]

Obesity is a complex disease attributable to many factors including genetics and environmental influences. Growing evidence suggests that gut microbiota is a major contributing factor to the pathogenesis of obesity and other metabolic disorders. This article reviews the current understanding of the role of gut microbiota in the regulation of energy balance and the development of obesity, and how the microbiota communicates with host tissues, in particular adipose tissue. We discuss several external factors that interfere with the interplay between gut microbiota and host tissue metabolism, including cold exposure, diet regimens, and genetic manipulations. We also review the role of diet-derived metabolites that regulate thermogenesis and thus energy homeostasis. Among the gut microbial metabolites, we emphasize short-chain fatty acids, which could be utilized by the host as a direct energy source while regulating the appetite of the host through the gut-brain axis. [ABSTRACT FROM AUTHOR]

The twin epidemics of obesity and type 2 diabetes (T2D) are a serious health, social, and economic issue. The dysregulation of adipose tissue biology is central to the development of these two metabolic disorders, as adipose tissue plays a pivotal role in regulating whole-body metabolism and energy homeostasis (1). Accumulating evidence indicates that multiple aspects of adipose biology are regulated, in part, by epigenetic mechanisms. The precise and comprehensive understanding of the epigenetic control of adipose tissue biology is crucial to identifying novel therapeutic interventions that target epigenetic issues. Here, we review the recent findings on DNA methylation events and machinery in regulating the developmental processes and metabolic function of adipocytes. We highlight the following points: 1) DNA methylation is a key epigenetic regulator of adipose development and gene regulation, 2) emerging evidence suggests that DNA methylation is involved in the transgenerational passage of obesity and other metabolic disorders, 3) DNA methylation is involved in regulating the altered transcriptional landscape of dysfunctional adipose tissue, 4) genome-wide studies reveal specific DNA methylation events that associate with obesity and T2D, and 5) the enzymatic effectors of DNA methylation have physiological functions in adipose development and metabolic function. [ABSTRACT FROM AUTHOR]

The article offers information on Alström syndrome (ALMS) is an extremely rare autosomal recessive disorder caused by mutations in ALMS has first reported in 1959 but has only been recognized as a ciliopathy. Topics include the ciliopathies comprise a group of human genetic diseases associated with primary cilia, and the microtubule-based organelles extending from the cell surface that transduce signals from the extracellular environment.

Insulin resistance is a sine qua non of type 2 diabetes and is associated with many other clinical conditions. Decades of research into mechanisms underlying insulin resistance have mostly focused on problems in insulin signal transduction and other mitochondrial and cytosolic pathways. By contrast, relatively little attention has been focused on transcriptional and epigenetic contributors to insulin resistance, despite strong evidence that such nuclear mechanisms play a major role in the etiopathogenesis of this condition. In this review, we summarize the evidence for nuclear mechanisms of insulin resistance, focusing on three transcription factors with a major impact on insulin action in liver, muscle, and fat. [ABSTRACT FROM AUTHOR]

Insulin resistance is a cardinal feature of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, ageing and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumour necrosis factor-α or by the steroid dexamethasone to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms. [ABSTRACT FROM AUTHOR]

Zfp521 is a novel antiadipogenic transcription factor that helps to determine the identity of a mesenchymal cell as bone or fat. [ABSTRACT FROM AUTHOR]

Canonical ubiquitin-like proteins (UBLs) such as ubiquitin, Sumo, NEDD8, and ISG15 are ligated to targets by E1-E2-E3 multienzyme cascades. The Sumo cascade, conserved among all eukaryotes, regulates numerous biological processes including protein localization, transcription, DNA replication, and mitosis. Sumo conjugation is initiated by the heterodimeric Aos1-Uba2 E1 enzyme (in humans called Sae1-Uba2), which activates Sumo's C-terminus, binds the dedicated E2 enzyme Ubc9, and promotes Sumo C-terminal transfer between the Uba2 and Ubc9 catalytic cysteines. To gain insights into details of E1-E2 interactions in the Sumo pathway, we determined crystal structures of the C-terminal ubiquitin fold domain (ufd) from yeast Uba2 (ufd), alone and in complex with Ubc9. The overall structures of both yeast ufd and Ubc9 superimpose well on their individual human counterparts, suggesting conservation of fundamental features of Sumo conjugation. Docking the ufd-Ubc9 and prior full-length human Uba2 structures allows generation of models for steps in Sumo transfer from Uba2 to Ubc9, and supports the notion that Uba2 undergoes remarkable conformational changes during the reaction. Comparisons to previous structures from the NEDD8 cascade demonstrate that UBL cascades generally utilize some parallel E1-E2 interaction surfaces. In addition, the structure of the ufd-Ubc9 complex reveals interactions unique to Sumo E1 and E2. Comparison with a previous Ubc9-E3 complex structure demonstrates overlap between Uba2 and E3 binding sites on Ubc9, indicating that loading with Sumo and E3-catalyzed transfer to substrates are strictly separate steps. The results suggest mechanisms establishing specificity and order in Sumo conjugation cascades. [ABSTRACT FROM AUTHOR]

Activation of canonical Wnt signaling inhibits brown adipogenesis of cultured cells by impeding induction of PPARγ and C/EBPα. Although enforced expression of these adipogenic transcription factors restores lipid accumulation and expression of FABP4 in Wnt-expressing cells, additional expression of PGC-1α is required for activation of uncoupling protein 1 (UCP1). Wntl0b blocks brown adipose tissue development and expression of UCP1 when expressed from the fatty acid binding protein 4 promoter, even when mice are administered a β3-agonist. In differentiated brown adipocytes, activation of Writ signaling suppresses expression of UCP1 through repression of PGC-1α. Consistent with these in vitro observations, UCP1-Wntl0b transgenic mice, which express Wntl0b in interscapular tissue, lack functional brown adipose tissue. While interscapular tissue of UCP1-Wntl0b mice lacks expression of PGC-lα and UCP1, the presence of unilocular lipid droplets and expression of white adipocyte genes suggest conversion of brown adipose tissue to white. Reciprocal expression of Wntl0b with UCP1 and PGC-lα in interscapular tissue from cold-challenged or genetically obese mice provides further evidence for regulation of brown adipocyte metabolism by Wnt signaling. Taken together, these data suggest that activation of canonical Wnt signaling early in differentiation blocks brown adipogenesis, whereas activating Wnt signaling in mature brown adipocytes stimulates their conversion to white adipocytes. [ABSTRACT FROM AUTHOR]

Obesity is a strong risk factor for insulin resistance. Chronic low-grade tissue inflammation and systemic inflammation have been proposed as major mechanisms that promote insulin resistance in obesity. Adipose tissue has been recognized as a nexus between inflammation and metabolism, but how exactly inflammatory gene expression is orchestrated during the development of obesity is not well understood. Epigenetic modifications are defined as heritable changes in gene expression and cellular function without changes to the original DNA sequence. The major epigenetic mechanisms include DNA methylation, histone modification, noncoding RNAs, nucleopositioning/remodeling and chromatin reorganization. Epigenetic mechanisms provide a critical layer of gene regulation in response to environmental changes. Accumulating evidence supports that epigenetics plays a large role in the regulation of inflammatory genes in adipocytes and adipose-resident immune cell types. This review focuses on the association between adipose tissue inflammation in obesity and major epigenetic modifications. [ABSTRACT FROM AUTHOR]

Summary Insulin resistance is a sine qua non of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, aging, and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumor necrosis factor-α (TNF) or by the steroid dexamethasone (Dex) to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms.

While there has been significant progress in determining the transcriptional cascade involved in terminal adipocyte differentiation, less is known about early events leading to lineage commitment and cell fate choice. It has been recently discovered that zinc finger protein 423 (Zfp423) is an early actor in adipose determination. Here, we show that a close paralog of Zfp423, Zfp521, acts as a key regulator of adipose commitment and differentiation in vitro and in vivo. Zfp521 exerts its actions by binding to early B cell factor 1 (Ebf1), a transcription factor required for the generation of adipocyte progenitors, and inhibiting the expression of Zfp423. Overexpression of Zfp521 in cells greatly inhibits adipogenic potential, whereas RNAi-mediated knock-down or genetic ablation of Zfp521 enhances differentiation. In addition, \(Zfp521^{−/−}\) embryos exhibit increased mass of interscapular brown adipose tissue and subcutaneous white adipocytes, a cell autonomous effect. Finally, Ebf1 participates in a negative feedback loop to repress Zfp521 as differentiation proceeds. Because Zfp521 is known to promote bone development, our results suggest that it acts as a critical switch in the commitment decision between the adipogenic and osteogenic lineages.

The transcription factor CCAAT/enhancer-binding protein a (C/EBPα) is required during adipogenesis for development of insulin-stimulated glucose uptake. Modes for regulating this function of C/EBPα have yet to be determined. Phosphorylation of C/EBPα on Ser-21 has been implicated in the regulation of granulopoiesis and hepatic gene expression. To explore the role of Ser-21 phosphorylation on C/EBPα function during adipogenesis, we developed constructs in which Ser-21 was mutated to alanine (S21A) to model dephosphorylation. In two cell culture models deficient in endogenous C/EBPα, enforced expression of S21A-C/EBPα resulted in normal lipid accumulation and expression of many adipogenic markers. However, S21A-C/EBPα had impaired ability to activate the GIut4 promoter specifically, and S21A-C/EBPα expression resulted in diminished GLUT4 and adiponectin expression, as well as reduced insulinstimulated glucose uptake. No defects in insulin signaling or GLUT4 vesicle trafficking were identified with S21A-C/EBPα expression, and when exogenous GLUT4 expression was enforced to normalize expression in S21A-C/EBPα cells, insulin-responsive glucose transport was reconstituted, suggesting that the primary defect was a deficit in GLUT4 levels. Mice in which endogenous C/EBPa was replaced with S21A-C/EBPα displayed reduced GLUT4 and adiponectin protein expression in epididymal adipose tissue and increased blood glucose compared with wild-type littermates. These results suggest that phosphorylation of C/EBPα on Ser-21 may regulate adipocyte gene expression and whole body glucose homeostasis. [ABSTRACT FROM AUTHOR]

Wnt is a family of secreted signaling proteins that regulate diverse developmental processes. Activation of canonical Wnt signaling by Wnt10b inhibits differentiation of preadipocytes in vitro. To determine whether Wnt signaling blocks adipogenesis in vivo, we created transgenic mice in which Wnt10b is expressed from the FABP4 promoter. Expression of Wnt10b in adipose impairs development of this tissue throughout the body, with a decline of ∼50% in total body fat and a reduction of ∼60% in weight of epididymal and perirenal depots. FABP4-Wntl0b mice resist accumulation of adipose tissue when fed a high fat diet. Furthermore, transgenic mice are more glucose-tolerant and insulin-sensitive than wild type mice. Expression of Wnt10b from the FABP4 promoter also blocks development of brown adipose tissue. Interscapular tissue of FABP4-Wnt10b mice has the visual appearance of white adipose tissue but expresses neither brown (e.g. uncoupling protein 1) nor white adipocyte markers. Transgenic mice are unable to maintain a core body temperature when placed in a cold environment, providing further evidence that Wntl0b inhibits development of brown adipose tissue. Although food intake is not altered in FABP4-Wntl0b mice, oxygen consumption is decreased. Thus, FABP4-Wntl0b mice on a chow diet gain more weight than controls, largely because of an increase in weight of skin. In summary, inhibition by Wnt10b of white and brown adipose tissue development results in lean mice without lipodystrophic diabetes. [ABSTRACT FROM AUTHOR]

Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remain unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone (DEX), a synthetic glucocorticoid. Treating wildtype (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue, and gastrocnemius (GA) muscle. This DEX effect was diminished in GA muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in GA muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced GA myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice, and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2a phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle. [ABSTRACT FROM AUTHOR]

The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat-fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis. [ABSTRACT FROM AUTHOR]

Brown fat can reduce obesity through the dissipation of calories as heat. Control of thermogenic gene expression occurs via the induction of various coactivators, most notably PGC-1α. In contrast, the transcription factor partner(s) of these cofactors are poorly described. Here, we identify interferon regulatory factor 4 (IRF4) as a dominant transcriptional effector of thermogenesis. IRF4 is induced by cold and cAMP in adipocytes and is sufficient to promote increased thermogenic gene expression, energy expenditure, and cold tolerance. Conversely, knockout of IRF4 in UCP1+ cells causes reduced thermogenic gene expression and energy expenditure, obesity, and cold intolerance. IRF4 also induces the expression of PGC-1α and PRDM16 and interacts with PGC-1α, driving Ucp1 expression. Finally, cold, β-agonists, or forced expression of PGC-1α are unable to cause thermogenic gene expression in the absence of IRF4. These studies establish IRF4 as a transcriptional driver of a program of thermogenic gene expression and energy expenditure. [ABSTRACT FROM AUTHOR]