Insulin-sensitizing Agents Research Articles

Androgen Receptor Roles in Insulin Resistance and Obesity in Males: The Linkage of Androgen-Deprivation Therapy to Metabolic Syndrome

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men. Androgen-deprivation therapy (ADT) is the first-line treatment and fundamental management for men with advanced PCa to suppress functions of androgen/androgen receptor (AR) signaling. ADT is effective at improving cancer symptoms and prolonging survival. However, epidemiological and clinical studies support the notion that testosterone deficiency in men leads to the development of metabolic syndrome that increases cardiovascular disease risk. The underlying mechanisms by which androgen/AR signaling regulates metabolic homeostasis in men are complex, and in this review, we discuss molecular mechanisms mediated by AR signaling that link ADT to metabolic syndrome. Results derived from various AR knockout mouse models reveal tissue-specific AR signaling that is involved in regulation of metabolism. These data suggest that steps be taken early to manage metabolic complications associated with PCa patients receiving ADT, which could be accomplished using tissue-selective modulation of AR signaling and by treatment with insulin-sensitizing agents.

Phosphatase and tension homolog overexpression in insulin resistant diabetic adipose tissue.

To investigate the expression of phosphatase and tension homolog (PTEN) in adipose tissue of KKAy diabetic mice, a mouse model of type 2 diabetes. KKAy diabetic mice were fed with high fat diet for 4 weeks. After blood glucose met the criteria of diabetes (over 16.7 mmol/L), mice were randomly divided into 3 groups: a control group (without any treatment), a rosiglitazone group (treated with rosiglitazone 12.5 mg/kg.d once per day), and a metformin group (treated with metformin 3 g/kg.d twice daily). After 4 weeks, we then determined the expression of PTEN and phosphoserine 473-Akt (pS473-Akt) in the epididymal adipose tissue with Western blots. The mice in each group were further divided into the insulin (-) subgroup and insulin (+) subgroup, which were intraperitoneally injected with saline and insulin (5 mU/g body weight), respectively. The expression of PTEN was elevated in the epididymal adipose tissue obtained from KKAy diabetic mice compared with that from the C57BL/6J mice (P<0.001). In accordance with the enhanced expression of PTEN, the level of pS473-Akt stimulated by insulin was decreased in the adipose tissue of KKAy mice compared to the C57BL/6J mice (P<0.001). Treatment with the insulin-sensitizing agents, rosiglitazone and metformin did not inhibit the elevated expression of PTEN in adipose tissue of KKAy diabetic mice. PTEN may play an important role in the development of insulin resistance in adipose tissue of type 2 diabetes mice model.

Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?

Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?

MicroRNA-29 fine-tunes the expression of key FOXA2-activated lipid metabolism genes and is dysregulated in animal models of insulin resistance and diabetes.

MicroRNAs (miRNAs) have emerged as biomarkers of metabolic status, etiological factors in complex disease, and promising drug targets. Recent reports suggest that miRNAs are critical regulators of pathways underlying the pathophysiology of type 2 diabetes. In this study, we demonstrate by deep sequencing and real-time quantitative PCR that hepatic levels of Foxa2 mRNA and miR-29 are elevated in a mouse model of diet-induced insulin resistance. We also show that Foxa2 and miR-29 are significantly upregulated in the livers of Zucker diabetic fatty (fa/fa) rats and that the levels of both returned to normal upon treatment with the insulin-sensitizing agent pioglitazone. We present evidence that miR-29 expression in human hepatoma cells is controlled in part by FOXA2, which is known to play a critical role in hepatic energy homeostasis. Moreover, we demonstrate that miR-29 fine-tunes FOXA2-mediated activation of key lipid metabolism genes, including PPARGC1A, HMGCS2, and ABHD5. These results suggest that miR-29 is an important regulatory factor in normal metabolism and may represent a novel therapeutic target in type 2 diabetes and related metabolic syndromes.

Metformin and other insulin sensitizers in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex disorder affecting a substantial group of women from adolescent to menopausal age groups. A substantial subgroup of these women exhibits increased insulin resistance. Insulin resistance is difficult to establish in clinical practice and many surrogate tests are available, although their value in the clinical setting is uncertain. The QUICKI method is an inexpensive and easy test to administer and is probably the best test to be used in PCOS patients, preferably in a clinical trial context. There is considerable evidence that insulin-sensitizing agents are not contributory to infertility management in the majority of women with PCOS. Currently, there is no evidence that cardiovascular morbidity is decreased by long-term use of insulin sensitizers in PCOS women.

Diabetes and dementia

s the population ages, attention has focused on the rise in the number of people suffering from dementia. Even the Prime Minister has taken on the Dementia Challenge and promised to double the money spent on research into dementia over the next 10 years. 1 Dementia is a feared condition and can have an overwhelming impact on the affected person as well as on family and carers. In contrast, the diagnosis of type 2 diabetes may be accepted with relative equanimity, causing more concern about change of lifestyle than alarm at the associated health risks. UK prevalences of dementia and diabetes are 800 000 and 3 million respectively, but the dominance of diabetes in older people means the risk of developing both conditions is significant. Interestingly, while the number of people with diabetes increases inexorably, there is good evidence that the frequency of dementia is plateauing, so that ‘later-born populations have a lower risk of prevalent dementia than those born earlier in the past century.’ 2 A leader in Practical Diabetes in April 2013 3 highlighted the shared pathogenesis between type 2 diabetes and dementia, raising the possibility that an insulin-sensitising agent might be useful in treating the insulin-resistant brain state seen in Alzheimer’s disease. In this article we discuss the interaction between diabetes and dementia and the role of education in helping people to care for these twin disorders.

Peroxisome Proliferator-Activated Receptor-γ Agonists Prevent Tumor Necrosis Factor-α-Mediated Inhibition of FSH-Induced Follicle Development and Estradiol Production in a Preantral Follicle Culture System

Although 60–80% of the women with polycystic ovary syndrome (PCOS) ovulate with clomiphene citrate (CC), the rest are CC-resistant. Recently, the use of insulin-sensitizing agents such as metformin and pioglitazone have been proposed for inducing ovulation in CC-resistant women with PCOS, and we have reported that administration of bezafibrate, a lipid-lowering fibrate, in addition to CC, successfully induced ovulation in CC-resistant women with PCOS and dyslipidemia. Both pioglitazone and bezafibrate are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists. This paper reviews the evidence for the direct effects of the drugs, which are PPAR-γ agonists, on follicle development and steroidogenesis, collected using an in vitro mouse preantral follicle culture system. We used the in vitro follicle culture system with the addition of tumor necrosis factor-alpha (TNF-α), which plays a role in insulin resistance, as a model for studying follicle development in women with PCOS. TNF-α inhibited FSH-induced follicle development and steroidogenesis in the follicle culture system. Both pioglitazone and bezafibrate prevented TNF-αmediated inhibition of FSH-induced follicle development and steroidogenesis through the PPAR-γ-stimulating pathway. Our results suggest that insulin-sensitizing drugs, especially PPAR-γ agonists, may directly influence follicle development and steroidogenesis in women with PCOS.

Effect of combination treatment of S–amlodipine with peroxisome proliferator-activated receptor agonists on metabolic and cardiovascular parameters in Zucker fa/fa rats

BackgroundType 2 diabetes is a complex metabolic disorder characterized by hyperglycemia, impaired glucose tolerance and insulin resistance associated with dyslipidemia and hypertension. The available drugs are not sufficiently efficacious in reducing cardiovascular risk and restoring normal glucose metabolism associated with type 2 diabetes as a mono- or a combination therapy. The present study examined the combined effects of an antihypertensive (S-Amlodipine) and an insulin-sensitizing agent, peroxisome proliferator-activated receptor (PPAR) agonists (Pioglitazone and Ragaglitazar), on cardiovascular risk factors in aged diabetic and insulin-resistant Zucker fa/fa rats.MethodsFollowing combination treatment for 14 days, blood pressure (BP), serum glucose, total cholesterol and triglycerides were measured. Aortic ring study was conducted to determine the effect of combination treatments on phenylephrine-induced vasoconstriction and acetylcholine (Ach)-induced vasorelaxation.ResultsIn combination, S-Amlodipine and Pioglitazone significantly reduced blood glucose (115.1 ± 6.6 vs. 81.7 ± 4.2), BP (184.4 ± 5.0 vs. 155.1 ± 5.0), serum triglycerides (362.5 ± 47.5 vs. 211.1 ± 23.7) and glucose intolerance when compared with vehicle treated Zucker fa/fa rats. Similar results were observed with the combination of S-Amlodipine and Ragaglitazar (Triglycerides, 362.5 ± 47.5 vs. 252.34 ± 27.86; BP, 184.4 ± 5.0 vs. 159.0 ± 8.0) except for serum glucose. ACh-induced vasorelaxation in aortic rings was also superior with both of the combinations compared to individual treatment. Furthermore, there was less body weight gain and food intake with S-Amlodipine and Pioglitazone combination in Zucker fa/fa rats. S-Amlodipine itself caused significant reduction in glucose (115.1 ± 6.6 vs. 89.7 ± 2.7) and BP (184.4 ± 5.0 vs. 156.1 ± 4.0) with improvement in insulin sensitivity observed through oral glucose tolerance test.ConclusionsThe results suggest that a combination of PPAR agonists and S-Amlodipine has partial benefits in improving the cardiovascular risk factors such as reduction in triglyceride levels, associated with chronic type 2 diabetes, and therefore may be utilized as an approach for addressing some of these devastating metabolic syndrome complications.

Impact of metformin treatment and swimming exercise on visfatin levels in high-fat-induced obesity rats.

Visfatin is a recently discovered adipocytokine that contributes to glucose and obesity-related conditions. Until now, its responses to the insulin-sensitizing agent metformin and to exercise are largely unknown. We aim to investigate the impact of metformin treatment and/or swimming exercise on serum visfatin and visfatin levels in subcutaneous adipose tissue (SAT), peri-renal adipose tissue (PAT) and skeletal muscle (SM) of high-fat-induced obesity rats. Sprague-Dawley rats were fed a normal diet or a high-fat diet for 16 weeks to develop obesity model. The high-fat-induced obesity model rats were then randomized to metformin (MET), swimming exercise (SWI), or adjunctive therapy of metformin and swimming exercise (MAS), besides high-fat obesity control group and a normal control group, all with 10 rats per group. Zoometric and glycemic parameters, lipid profile, and serum visfatin levels were assessed at baseline and after 6 weeks of therapy. Visfatin levels in SAT, PAT and SM were determined by Western Blot. Metformin and swimming exercise improved lipid profile, and increased insulin sensitivity and body weight reduction were observed. Both metformin and swimming exercise down-regulated visfatin levels in SAT and PAT, while the adjunctive therapy conferred greater benefits, but no changes of visfatin levels were observed in SM. Our results indicate that visfatin down-regulation in SAT and PAT may be one of the mechanisms by which metformin and swimming exercise inhibit obesity.

Peroxisome proliferator-activated receptor activating hypoglycemic effect of Gardenia jasminoides Ellis aqueous extract and improvement of insulin sensitivity in steroid induced insulin resistant rats

BackgroundThe active components of Gardenia (Gardenia jasminoides Ellis, GJ) exhibit a hypoglycemic effect by improving insulin secretion and lowering plasma lipids. In the present study, we fed a water extract of gardenia to steroid-induced insulin-resistant (SIIR) rats and observed changes in signaling proteins in order to elucidate the mechanisms of the insulin-sensitizing effect of GJ and evaluate its possibility as an insulin-sensitizing agent.MethodsNormal Wistar rats were randomly divided into a control group (i.e., saline) and experimental groups (GJ 100 and 200 mg/kg). Blood samples were taken at 0, 30, and 60 min for plasma glucose assay in order to determine the optimal dose to induce the hypoglycemic effect. SIIR rats were then randomly divided into a control group (i.e., saline) and an experimental group (optimal dose of gardenia extract) to observe the insulin-sensitizing effect of the extract. Finally, western blot analysis was performed to detect intracellular signaling proteins to elucidate the mechanisms of the insulin-sensitization effect of GJ.ResultsThe normal Wistar rats in the GJ 200 mg/kg group exhibited significant hypoglycemic activity. Meanwhile, the SIIR rats had higher plasma glucose levels than normal rats. There was no obvious change in insulin level, but the insulin sensitivity index and homeostasis model assessment index were significantly elevated. Meanwhile, a significant hypoglycemic effect was observed with GJ 200 mg/kg. In addition, intracellular signaling proteins including insulin receptor substrate-1 (IRS-1) and peroxisome proliferator-activated receptor (PPARγ) were elevated in muscle cells.ConclusionsThe optimal dose of GJ aqueous extract of 200 mg/kg exerts a PPARγ-activating hypoglycemic effect and improves insulin resistance in SIIR rats. Therefore, it is a potential insulin-sensitizing agent in type 2 diabetes mellitus with insulin resistance.

The endothelial protective effects of pioglitazone on insulin resistance in endothelial cells.

Insulin resistance plays an important role in vascular endothelial damage and atherosclerosis. Pioglitazone is an insulin-sensitizing agent and can reduce insulin resistance. In this study, the cellular model of insulin resistance was used to investigate the mechanisms involved in the endothelial protective effects of pioglitazone in a vascular endothelial cell damage model. The results showed that pioglitazone could effectively increase the survival rate of human umbilical vein endothelial cells (ECV), reduce apoptosis, and relieve insulin resistance damage. To understand the endothelial protective effect mechanisms of pioglitazone, we showed that 50 ng/mL and 100 ng/mL of pioglitazone could upregulate the levels of inducible nitric oxide synthase (NOS) and pioglitazone could induce NO levels. These results suggested that pioglitazone could have endothelial protective effects in a vascular endothelial cell damage model of insulin resistance and used to prevent beforehand and treat a vascular endothelial cell damage of insulin resistance.

Polycystic ovarian disease in adult and perimenopausal women

Polycystic ovarian disease (PCOD) is most common endocrine disorder in women. Symptoms are variable and often involve more than one body function. The major clinical features are hirsutism, menstrual irregularities, obesity, insulin resistance, hyperinsulinemia, polycystic ovaries (PCO). Other characteristics include malepattern balding, acanthosis negricans, sleep apnea with increased risk for hypertension, cardiovascular disease, diabetes mellitus, endometrial carcinoma, and overproduction of ovarian androgens and luteinizing hormone. While some believe that PCOD disappears after menopause, symptoms can persist after menopause. The cause of PCOD is still unknown. Genetic studies suggest that transmission is autosomal dominant with decreased penetrance because of hypersensitive intra-ovarian-insulin-androgen signaling with disturbances in gonadotropin levels, hyperandrogenism, and reduced insulin sensitivity. Hyperinsulinaemia frequently stimulates lipid storage with alterations in lipoproteins, cholesterol, hyperlipidaemia obesity. Anti-Mullerian hormone might be responsible for these abnormalities. Information on PCOD in adult perimenopausal women is scarce as it may be difficult to diagnose, since one marker is irregular menstruation. PCO, a common feature of PCOD, may occur with or without other disorders and the associated obesity is of android (central) type with a waist-hip ratio (WHR) of > 0.8. Fasting glucose insulin ratio (FGI) has become a popular diagnostic criteria. Triglycerides, low-density lipoprotein (LDL), and cholesterol are elevated with decreased levels of sex hormone binding globulin (SHBG) due to hyperinsulinemia. The elevated levels of serum leptin and insulin and their linkage to obesity suggest the potentially complicated implications for obese patients. Preventative measures for PCOD are limited. Clinical management is primarily focused on treating symptoms and manifestations and preventing long-term complications. Oral contraceptive pills (OCP) have several benefits, including treatment of irregular menstruation. Insulin-sensitizing agents can ameliorate insulin resistance, endocrine, and metabolic reproductive abnormalities. Metformin has been extensively used and is not associated with an increase in insulin secretion or risk of hypoglycaemia. The weight loss that accompanies protracted therapy may account for some of the beneficial effects. Long-term follow-up is needed to determine the effectiveness in changing the metabolic outcomes without causing other complications, such as reducing hair growth. Management should include patient education, with particular attention to diabetes, cardiovascular risk, obesity and endometrial cancer.

Modern approach to the clinical management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common and emerging form of chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to steatohepatitis, which may progress to cirrhosis, liver cancer, and liver mortality. Common metabolic diseases, which are well established cardiovascular risk factors, have been associated to NAFLD and cardiovascular disease is the single most important cause of morbidity and mortality in this patient population. The pathogenesis of NAFLD appears multifactorial and many mechanisms have been proposed as possible causes of fatty liver infiltration. Management of fatty liver has become a major challenge to healthcare systems as the consequence of the increasing rates of obesity worldwide. First-line management focuses on lifestyle modifications. Moderate weight reduction either by dietary restriction or by increased habitual physical activity is safe and highly recommended. Several therapeutic interventions have been proposed. These include insulin sensitizer agents, lipid lowering drugs, antioxidants such as vitamin E and supplementation of vitamin D3. However, therapeutic strategies have been largely empirical so far, and experimental trials have mostly been carried out in uncontrolled settings with small sample sizes. Metabolic conditions such as diabetes mellitus, obesity, hypertension and hyperlipidemia, should be strongly considered and a multidisciplinary approach should be personalized for individual patients. Treatment of co-morbidities should be regarded as of paramount importance in the management of these patients. The purpose of this review is to examine different approaches for the clinical management of non-alcoholic fatty liver disease.

Synthesis of N-(6-(4-(Piperazin-1-yl)phenoxy)pyridin-3-yl)benzenesulfonamide Derivatives for the Treatment of Metabolic Syndrome.

Metabolic syndrome is a widely prevalent multifactorial disorder associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. High plasma levels of insulin and glucose due to insulin resistance are a major component of the metabolic disorder. Thiazolidinediones (TZDs) are potent PPARγ ligand and used as insulin sensitizers in the treatment of type 2 diabetes mellitus. They are potent insulin-sensitizing agents but due to adverse effects like hepatotoxicity, a safer alternative of TZDs is highly demanded. Here we report synthesis of N-(6-(4-(piperazin-1-yl)phenoxy)pyridin-3-yl)benzenesulfonamide derivatives as an alternate remedy for insulin resistance.

Effect of naringenin on brain insulin signaling and cognitive functions in ICV-STZ induced dementia model of rats

Recent evidence indicates that severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease pathology. It has been reported that naringenin (NAR), derived from citrus aurantium, exhibits antioxidant potential and protects the brain against neurodegeneration. The current study was designed to further investigate the protective effect of the NAR on neurodegeneration in a rat model of AD induced by an intracerebroventricular (ICV) injection of streptozotocin (STZ), and to determine whether this neuroprotective effect was associated with brain insulin signaling. Rats were injected bilaterally with ICV-STZ (3 mg/kg), while sham rats received the same volume of vehicle and then supplemented with NAR (25, 50 mg, 100 mg/kg, respectively) for 3 weeks. The ICV-STZ injected rats did not have elevated blood glucose levels. 21 days following ICV-STZ injection, rats treated with NAR had better learning and memory performance in the Morris water maze test compared with rats treated with saline. We demonstrated that NAR increased the mRNA expression of INS and INSR in cerebral cortex and hippocampus. In addition, NAR reversed ICV-STZ induced Tau hyper-phosphorylation in both hippocampus and cerebral cortex through downregulation of glycogen synthase kinase-3β (GSK-3β) activity, a key kinase in the insulin signaling. Brain levels of Abeta, which were elevated in ICV-STZ rats, were significantly reduced in NAR-treated rats via upregulation of insulin degrading enzyme. These effects were mediated by increased insulin and insulin receptors expression in the brain, suggesting that insulin sensitizer agents might have therapeutic efficacy in early AD.

Pharmacological agents for nonalcoholic steatohepatitis.

The rationale for specific pharmacologic therapy in nonalcoholic steatohepatitis (NASH) is determined by the potential for disease progression and the difficulties, in many patients, to successfully implement diet and lifestyle changes in the long term. Because they correct insulin resistance, insulin-sensitizing agents are attractive candidates for the treatment of NASH. However, two randomized studies have shown that vitamin E, despite having no effect on insulin sensitivity, achieves interesting histological and biochemical efficacy. This review provides an insight into the therapeutic efficacy and safety issues of different pharmacological agents tested in human NASH.

PPAR-Gamma in Ulcerative Colitis: A Novel Target for Intervention

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor, originally described in adipose tissue, that controls the expression of a large number of regulatory genes in lipid metabolism and insulin sensitization. Well known by endocrinologists, thiazolidinediones (TZDs) are classical PPARγ synthetic agonists which were currently used as insulin-sensitizing agents in the treatment of type 2 diabetes. While the clinical benefits of TZDs in treating metabolic disorders have been clearly demonstrated, new studies performed in animal models of colitis and in patients with ulcerative colitis have also revealed the key roles of PPARγ activation in the regulation of inflammation and immune response, notably in the colon through epithelial cells. During inflammation, PPAR acts directly to negatively regulate gene expression of proinflammatory genes in a ligand-dependent manner by antagonizing the activities of other transcription factors such as members of the NF-κB and AP-1 families. A major mechanism that underlies the ability of PPARs to interfere with the activities of these transcription factors has been termed transrepression. PPARγ acts by inhibiting signaldependent transcription factors that mediate inflammatory programs of gene activation. However, due to safety issues concerning particularly the greater risk of myocardial infarction, use of TZDs has been severely limited for the treatment of type 2 diabetes and/or inflammatory diseases, justifying the development of a new family of PPARγ agonists with major transrepressive effects and without toxicity. By the demonstration that the anti-inflammatory effects of 5- aminosalicylic acid (5-ASA) in patients with ulcerative colitis were mediated by PPARγ activation, several molecules having 5-ASA similarities have been developed and screened leading to the selection of a aminophenyl-alpha-methoxypropionic acids named GED-0507-34-Levo (GED). This compound activating PPARγ has 100-to 150-fold higher anti-inflammatory activity than 5-ASA. This new PPAR modulator is giving promising results both in vitro and in vivo, without toxicity and is currently evaluated in a phase 2 clinical trial. The aim of this review is to present and discuss the evidence suggesting that PPARγ targeting is of therapeutic interest in the treatment of UC.

Metformin in Diabetic Patients with Heart Failure: Safe and Effective?

Management of diabetic patients with heart failure is a complex endeavor. The initial reluctance to use metformin in these patients has given way to a broader acceptance after clinical trials and meta-analyses have revealed that some of the insulin-sensitizing agents lead to adverse cardiovascular events. We have proposed that an increase of substrate uptake by the insulin-resistant heart is detrimental because the heart is already flooded with fuel. In light of this evidence, metformin offers a unique safety profile in the patient with diabetes and heart failure. Our article expands on the use of metformin in patients with heart failure. We propose that the drug targets both the source as well as the destination (in this case the heart) of excess fuel. We consider treatment of diabetic heart failure patients with metformin both safe and effective.

Insulin resistance protects the heart from fuel overload in dysregulated metabolic states

Reversing impaired insulin sensitivity has been suggested as treatment for heart failure. However, recent clinical evidence suggests the opposite. Here we present a line of reasoning in support of the hypothesis that insulin resistance protects the heart from the consequences of fuel overload in the dysregulated metabolic state of obesity and diabetes. We discuss pathways of myocardial fuel toxicity, as well as several layers of defense against fuel overload. Our reassessment of the literature suggests that in the heart, insulin-sensitizing agents result in an elimination of some of the defenses, leading to cytotoxic damage. In contrast, a normalization of fuel supply should either prevent or reverse the process. Taken together, we offer a new perspective on insulin resistance of the heart.

Exercise as a therapeutic tool to prevent mitochondrial degeneration in nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease, encompassing hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, is a significant health problem associated with modern lifestyle, based on caloric overconsumption and physical inactivity. Although the mechanisms associated with progression from the 'benign' steatosis to NASH are still elusive, mitochondrial dysfunction seems to play an important role in this degenerative process. Degeneration of mitochondrial function during NASH has been associated with impaired β-oxidation, oxidative phosphorylation and increased reactive oxygen species production, contributing to hepatocyte death and inflammatory response. Despite the fact that several therapeutic approaches can be used in the context of NASH, including insulin-sensitizing agents, anti-obesity drugs, lipid-lowering drugs or mitochondrial-targeted drugs, dietary and physical activity are still the most effective strategies. In fact, active lifestyles decrease insulin resistance and body weight and result in decreased histological signs of liver injury. In fatty liver, physical activity prevents the disease progression through mitochondrial adaptations, namely by increasing cytochrome c content, enzyme activities and fatty acid oxidation, which are lost after some days of physical inactivity. However, less is known about the effect of physical activity on NASH-associated mitochondrial dysfunction. After a brief characterization of NASH and its association with liver mitochondrial (dys)function, the present review addresses the impact of physical (in)activity on NASH and, particularly, the possible contribution of active lifestyles to the modulation of liver mitochondrial dysfunction.