Abstract: PGC-1alpha is a coactivator of nuclear receptors and other transcription factors that regulates several metabolic processes, including mitochondrial biogenesis and respiration, hepatic gluconeogenesis, and muscle fiber-type switching. We show here that, while hepatocytes lacking PGC-1alpha are defective in the program of hormone-stimulated gluconeogenesis, the mice have constitutively activated gluconeogenic gene expression that is completely insensitive to normal feeding controls. C/EBPbeta... Show More
Abstract: While it has been known for more than 75 years that physical activity is associated with increased mitochondrial content in muscle, the molecular mechanism for this adaptive process has only recently been elucidated. This brief review examines existing studies that have identified AMPK-activated protein kinase (AMPK) and several other key regulators of mitochondrial biogenesis, including peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta,... Show More
Abstract: Recent studies have demonstrated a strong relationship between aging-associated reductions in mitochondrial function, dysregulated intracellular lipid metabolism, and insulin resistance. Given the important role of the AMP-activated protein kinase (AMPK) in the regulation of fat oxidation and mitochondrial biogenesis, we examined AMPK activity in young and old rats and found that acute stimulation of AMPK-alpha(2) activity by 5'-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR)... Show More
Full-text available · Article · Mar 2007 · Cell Metabolism
Abstract: Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and is strongly associated with obesity. Increased concentrations of intracellular fatty acid metabolites have been postulated to interfere with insulin signaling by activation of a serine kinase cascade involving PKCtheta in skeletal muscle. Uncoupling protein 3 (UCP3) has been postulated to dissipate the mitochondrial proton gradient and cause metabolic inefficiency. We therefore hypothesized that overexpression of... Show More
Full-text available · Article · Aug 2007 · Journal of Clinical Investigation
Abstract: Acetyl–CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2 −/− and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulin-stimulated liver and muscle glucose metabolism during a hyperinsulinemic–euglycemic clamp in Acc2 −/− and WT control mice fed... Show More
Full-text available · Article · Nov 2007 · Proceedings of the National Academy of Sciences
Abstract: Insulin resistance in skeletal muscle plays a critical role in the pathogenesis of type 2 diabetes, yet the cellular mechanisms responsible for insulin resistance are poorly understood. In this study, we examine the role of serine phosphorylation of insulin receptor substrate (IRS)-1 in mediating fat-induced insulin resistance in skeletal muscle in vivo.
To directly assess the role of serine phosphorylation in mediating fat-induced insulin resistance in skeletal muscle, we generated... Show More
Full-text available · Article · Oct 2008 · Diabetes
Abstract: Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1α in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1α expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy... Show More
Full-text available · Article · Jan 2009 · Proceedings of the National Academy of Sciences
In addition, the acetylation of mitochondrial proteins may represent another AMPK-independent feedback mechanism. The study provides a mechanism for insulin resistance in the condition of ATP surplus in human and mouse [10, 11]. Our data suggest a new mechanism for the insulin-sensitizing activities of anti-diabetic medicines such as metformin and berberine, which inhibit ATP production in mitochondria .
[Show abstract] [Hide abstract] ABSTRACT: It is generally accepted that ATP regulates mitochondrial function through the AMPK signaling pathway. However, the AMPK-independent pathway remains largely unknown. In this study, we investigated ATP surplus in the negative regulation of mitochondrial function with a focus on pyruvate dehydrogenase (PDH) phosphorylation and protein acetylation. PDH phosphorylation was induced by a high fat diet in the liver of obese mice, which was associated with ATP elevation. In 1c1c7 hepatoma cells, the phosphorylation was induced by palmitate treatment through induction of ATP production. The phosphorylation was associated with a reduction in mitochondria oxygen consumption after 4 h treatment. The palmitate effect was blocked by etomoxir, which inhibited ATP production through suppression of fatty acid β-oxidation. The PDH phosphorylation was induced by incubation of mitochondrial lysate with ATP in vitro without altering the expression of PDH kinase 2 (PDK2) and 4 (PDK4). In addition, acetylation of multiple mitochondrial proteins was induced by ATP in the same conditions. Acetyl-CoA exhibited a similar activity to ATP in induction of the phosphorylation and acetylation. These data suggest that ATP elevation may inhibit mitochondrial function through induction of the phosphorylation and acetylation of mitochondrial proteins. The results suggest an AMPK-independent mechanism for ATP regulation of mitochondrial function.
Indeed, TH derivatives promote cell autonomous beiging in WAT depots that correlates with generally improved metabolic profile and normalization of hyperglycaemia (Lin et al. 2015). Overexpression of UCP3 in skeletal muscle protects against insulin resistance induced by high-fat diet and promotes body weight loss (Himms-Hagen & Harper 2001, Sbraccia et al. 2002, Choi et al. 2007). Since UCP1 mRNA and UCP3 mRNA were strongly induced by T3 and 3,5-T2 in WAT and skeletal muscle, respectively, we propose that increased substrate utilization could also contribute to 3,5-T2-dependent reductions in blood glucose.
[Show abstract] [Hide abstract] ABSTRACT: Aim:
Thyroid hormones regulate metabolic response. While triiodothyronine (T3) is usually considered to be the active form of thyroid hormone, one form of diiodothyronine (3,5-T2) exerts T3-like effects on energy consumption and lipid metabolism. 3,5-T2 also improves glucose tolerance in rats and 3,5-T2 levels correlate with fasting glucose in humans. Presently, however, little is known about mechanisms of 3,5-T2 effects on glucose metabolism. Here, we set out to compare effects of T3, 3,5-T2 and another form of T2 (3,3-T2) in a mouse model of diet induced obesity and determined effects of T3 and 3,5-T2 on markers of classical insulin sensitization to understand how diiodothyronines influence blood glucose.
Cell and protein based assays of thyroid hormone action. Assays of metabolic parameters in mice. Analysis of transcript and protein levels in different tissues by qRT-PCR and western blot.
T3 and 3,5-T2 both reduce body weight, adiposity and body temperature despite increased food intake. 3,3'-T2 lacks these effects. T3 and 3,5-T2 reduce blood glucose levels whereas 3,3'-T2 worsens glucose tolerance. Neither T3 or 3,5-T2 affects markers of insulin sensitization in skeletal muscle or white adipose tissue (WAT) but both reduce hepatic GLUT2 glucose transporter levels and glucose output. T3 and 3,5-T2 also induce expression of mitochondrial uncoupling proteins (UCPs) 3 and 1 in skeletal muscle and WAT, respectively.
3,5-T2 influences glucose metabolism in a manner that is distinct from insulin sensitization and involves reductions in hepatic glucose output and changes in energy utilization. This article is protected by copyright. All rights reserved.
In our study, mitochondrial biogenesis and mitochondrial fusion and fission may have no effect on the changes in aorta with exercise training, since the expression of PGC-1α, Mfn1, and Drp1 was not changed in exercised mice compared mice without exercise. In contrast, previous studies suggest that AMPK works through PGC-1α to promote mitochondrial biogenesis in acute exercise in skeletal muscles (Kahn et al., 2005; Reznick and Shulman, 2006), and that endurance training increases Mfn1 content to induce mitochondrial fusion in rat liver (Gonçalves et al., 2016). These results suggest that mitochondrial content may be regulated through different signaling pathways in different cells in exercise training.
[Show abstract] [Hide abstract] ABSTRACT: Chronic exercise training is known to protect the vasculature; however, the underlying mechanisms remain obscure. The present study hypothesized that exercise may improve aortic endothelial and mitochondrial function through an adenosine monophosphate-activated protein kinase α2 (AMPKα2)-dependent manner. Ten-week-old AMPKα2 knockout (AMPKα2−/−) mice and age-matched wild-type (WT) mice were subjected to daily treadmill running for 6 weeks, and the thoracic aorta from these mice were used for further examination. Our results showed that exercise significantly promoted vasodilatation and increased expression and phosphorylation of endothelial nitric oxide synthase (eNOS), concomitant with increased AMPKα2 expression in WT mice. These effects were not observed in AMPKα2−/− mice. Furthermore, exercise training increased thoracic aortic mitochondrial content as indicated by increased Complex I and mitochondrial DNA (mtDNA) in WT mice but not in AMPKα2−/− mice. This may be caused by decreased mitochondrial autophagy since the expression of BH3 domain-containing BCL2 family members BNIP3-like (BNIP3L) and LC3B were decreased in WT mice with exercise. And these changes were absent with AMPKα2 deletion in mice. Importantly, exercise increased the expression of manganous superoxide dismutase (MnSOD) and catalase, suggesting that mitochondrial antioxidative capacity was increased. Notably, the improved antioxidative capacity was lost in AMPKα2−/− mice with exercise. In conclusion, this study illustrated that AMPKα2 plays a critical role in exercise-related vascular protection via increasing endothelial and mitochondrial function in the artery.
In lean mice, insulin potently induced tyrosine phosphorylation of IRS1, and increased the level of IRS1-associated p85 subunit of PI3K (Fig. S1A) [41, 47]. Compared to lean M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Adropin therapy alleviates glucose intolerance 12 muscle, these increases were diminished in muscle of DIO mice (Fig. S1A) [41, 47] . Unexpectedly, adropin pretreatment did not restore the diminished responses of IRS1 and PI3K despite that it enhanced Akt signaling actions (Fig. S1A andFig.
[Show abstract] [Hide abstract] ABSTRACT: The peptide hormone adropin regulates fuel selection preferences in skeletal muscle under fed and fasted conditions. Here, we investigated whether adropin treatment can ameliorate the dysregulation of fuel substrate metabolism, and improve aspects of glucose homeostasis in diet-induced obesity (DIO) with insulin resistance.
DIO C57BL/6 mice maintained on a 60% kcal fat diet received five intraperitoneal (i.p.) injections of the bioactive peptide adropin(34-76) (450 nmol/kg/i.p.). Following treatment, glucose tolerance and whole body insulin sensitivity were assessed and indirect calorimetry was employed to analyze whole body substrate oxidation preferences. Biochemical assays performed in skeletal muscle samples analyzed insulin signaling action and substrate oxidation.
Adropin treatment improved glucose tolerance, enhanced insulin action and augmented metabolic flexibility towards glucose utilization. In muscle, adropin treatment increased insulin-induced Akt phosphorylation and cell-surface expression of GLUT4 suggesting sensitization of insulin signaling pathways. Reduced incomplete fatty acid oxidation and increased CoA/acetyl-CoA ratio suggested improved mitochondrial function. The underlying mechanisms appear to involve suppressions of carnitine palmitoyltransferase-1B (CPT-1B) and CD36, two key enzymes in fatty acid utilization. Adropin treatment activated pyruvate dehydrogenase (PDH), a rate-limiting enzyme in glucose oxidation, and downregulated PDH kinase-4 (PDK-4) that inhibits PDH. Along with these changes, adropin treatment downregulated peroxisome proliferator-activated receptor-gamma coactivator-1α that regulates expression of Cpt1b, Cd36 and Pdk4.
Adropin treatment of DIO mice enhances glucose tolerance, ameliorates insulin resistance and promotes preferential use of carbohydrate over fat in fuel selection. Skeletal muscle is a key organ in mediating adropin's whole-body effects, sensitizing insulin signaling pathways and altering fuel selection preference to favor glucose while suppressing fat oxidation.
Diets high in saturated fatty acids are more obesogenic than mono-and polyunsaturated as the saturated fatty acids are inefficiently used for energy production and are therefore more readily stored . Furthermore, long-chain fatty acids  Additional phenotypes Hyperglycemic clamp Identifies glucose sensitivity, by measuring serum insulin levels  Hyperinsulinemic-euglycemic clamp Considerations are time of clamp and how tightly to regulate the glucose infusions [44, 52, 53] Determines glucose use Tissue specific glucose uptake Used in conjunction with the above clamp techniques  Requires an MRI and radioactively labeled energy sources Much easier in rats Determines insulin sensitivity in multiple tissues Inflammation
[Show abstract] [Hide abstract] ABSTRACT: Type 2 diabetes mellitus (T2DM) is a worldwide epidemic, which by all predictions will only increase. To help in combating the devastating array of phenotypes associated with T2DM a highly reproducible and human disease-similar mouse model is required for researchers. The current options are genetic manipulations to cause T2DM symptoms or diet induced obesity and T2DM symptoms. These methods to model human T2DM have their benefits and their detractions. As far as modeling the majority of T2DM cases, HFD establishes the proper etiological, pathological, and treatment options. A limitation of HFD is that it requires months of feeding to achieve the full spectrum of T2DM symptoms and no standard protocol has been established. This paper will attempt to rectify the last limitation and argue for a standard group of HFD protocols and standard analysis procedures.
Though surprising, based on the overall protective properties of the PINK1/Parkin pathway, these effects may be explained by tissue-specific differences in expression: Parkin and PINK1 protein levels were found to be increased in blood vessels of HFD mice (Wu et al., 2015), whereas a significant loss of Parkin was found in the SN of these mice (Khang et al., 2015). In SN of HFD mice, Parkin deficiency led to accumulation of the Parkin substrate, PARIS, and a reduction of PGC-1α (Khang et al., 2015), which in addition to regulating mitochondrial biogenesis, is also known to act as a powerful regulator of systemic metabolic homeostasis (Lin et al., 2004). Overexpression of PGC-1α in cell models decreased lipid-droplet accumulation and increased mitochondrial fatty acid oxidation and downregulation of PINK1 abolished these effects (Choi et al., 2014).
[Show abstract] [Hide abstract] ABSTRACT: Parkinson's disease (PD) is one of the most frequent neurodegenerative disease caused by the preferential, progressive degeneration of the dopaminergic (DA) neurons of the substantia nigra (SN) pars compacta. PD is characterized by a multifaceted pathological process involving protein misfolding, mitochondrial dysfunction, neuroinflammation and metabolism deregulation. The molecular mechanisms governing the complex interplay between the different facets of this process are still unknown. PARK2/Parkin and PARK6/PINK1, two genes responsible for familial forms of PD, act as a ubiquitous core signaling pathway, coupling mitochondrial stress to mitochondrial surveillance, by regulating mitochondrial dynamics, the removal of damaged mitochondrial components by mitochondria-derived vesicles, mitophagy, and mitochondrial biogenesis. Over the last decade, PINK1/Parkin-dependent mitochondrial quality control emerged as a pleiotropic regulatory pathway. Loss of its function impinges on a number of physiological processes suspected to contribute to PD pathogenesis. Its role in the regulation of innate immunity and inflammatory processes stands out, providing compelling support to the contribution of non-cell-autonomous immune mechanisms in PD. In this review, we illustrate the central role of this multifunctional pathway at the crossroads between mitochondrial stress, neuroinflammation and metabolism. We discuss how its dysfunction may contribute to PD pathogenesis and pinpoint major unresolved questions in the field.
Indeed, activation of the AMPK cascade has been associated with the improvement of glucose and lipid metabolism, with the inhibition of platelet aggregation and thrombi reduction, as well as with neuroprotective and anticancer effects (Takikawa, Inoue, Horio, & Tsuda, 2010;Park, Lee, Lee, Park, & Kim, 2014;Lee, Lee, Kim, & Park, 2010;Zhang, Wang, Wang, Liu, & Xia, 2013). Furthermore, the contribution of aging-associated reductions of AMPK activity in mitochondrial dysfunction and increased oxidative damage associated with aging has been already advanced (Reznick et al., 2007). Dietary polyphenols have been recently proposed as activators of the AMPK signaling pathway, and this fact might explain the relationship between consumption of polyphenol-rich foods, disease prevention, and the slowdown of aging progression (Gasparrini et al., 2015).
[Show abstract] [Hide abstract] ABSTRACT: Dietary polyphenols have been recently proposed as activators of the AMP-activated protein kinase (AMPK) signaling pathway and this fact might explain the relationship between the consumption of polyphenol-rich foods and the slowdown of the progression of aging. In the present work, the effects of strawberry consumption were evaluated on biomarkers of oxidative damage and on aging-associated reductions in mitochondrial function and biogenesis for 8 weeks in old rats. Strawberry supplementation increased antioxidant enzyme activities, mitochondrial biomass and functionality, and decreased intracellular ROS levels and biomarkers of protein, lipid and DNA damage (P < 0.05). Furthermore, a significant (P < 0.05) increase in the expression of the AMPK cascade genes, involved in mitochondrial biogenesis and antioxidant defenses, was also detected after strawberry intake. These in vivo results were then verified in vitro on HepG2 cells, confirming the involvement of AMPK in the beneficial effects exerted by strawberry against aging progression.