Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy.

The highly prevalent metabolic dysfunction-associated steatohepatitis (MASH) is associated with liver steatosis, inflammation, and hepatocyte injury, which can lead to fibrosis and may progress to hepatocellular carcinoma and death. New treatment modalities such as gene therapy may be transformative for MASH patients. Here, we describe that one-time intramuscular administration of adeno-associated viral vectors of serotype 1 (AAV1) encoding native fibroblast growth factor 21 (FGF21), a key metabolic regulator, resulted in sustained increased circulating levels of the factor, which mediated long-term (>1 year) MASH and hepatic fibrosis reversion and halted development of liver tumors in obese male and female mouse models.

Integrated gene expression profiles reveal a transcriptomic network underlying the thermogenic response in adipose tissue.

Obesity and type 2 diabetes are two closely related diseases representing a serious threat worldwide. An increase in metabolic rate through enhancement of non-shivering thermogenesis in adipose tissue may represent a potential therapeutic strategy. Nevertheless, a better understanding of thermogenesis transcriptional regulation is needed to allow the development of new effective treatments.

AAV-mediated BMP7 gene therapy counteracts insulin resistance and obesity.

Type 2 diabetes, insulin resistance, and obesity are strongly associated and are a major health problem worldwide. Obesity largely results from a sustained imbalance between energy intake and expenditure. Therapeutic approaches targeting metabolic rate may counteract body weight gain and insulin resistance.

BMP7 overexpression in adipose tissue induces white adipogenesis and improves insulin sensitivity in ob/ob mice.

Background/objectives: During obesity, hypertrophic enlargement of white adipose tissue (WAT) promotes ectopic lipid deposition and development of insulin resistance. In contrast, WAT hyperplasia is associated with preservation of insulin sensitivity. The complex network of factors that regulates white adipogenesis is not fully understood.

Vitamin D Receptor Overexpression in β-Cells Ameliorates Diabetes in Mice.

Vitamin D deficiency has been associated with increased incidence of diabetes, both in humans and in animal models. In addition, an association between vitamin D receptor (VDR) gene polymorphisms and diabetes has also been described. However, the involvement of VDR in the development of diabetes, specifically in pancreatic β-cells, has not been elucidated yet.

FGF21 gene therapy as treatment for obesity and insulin resistance.

Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity.

AAV-mediated overexpression in skeletal muscle activates oxidative capacity but does not prevent insulin resistance.

Type 2 diabetes is characterized by triglyceride accumulation and reduced lipid oxidation capacity in skeletal muscle. SIRT1 is a key protein in the regulation of lipid oxidation and its expression is reduced in the skeletal muscle of insulin resistant mice. In this tissue, up-regulates the expression of genes involved in oxidative metabolism and improves mitochondrial function mainly through PPARGC1 deacetylation.

HMGA1 overexpression in adipose tissue impairs adipogenesis and prevents diet-induced obesity and insulin resistance.

High-Mobility-Group-A1 (HMGA1) proteins are non-histone proteins that regulate chromatin structure and gene expression during embryogenesis, tumourigenesis and immune responses. In vitro studies suggest that HMGA1 proteins may be required to regulate adipogenesis. To examine the role of HMGA1 in vivo, we generated transgenic mice overexpressing HMGA1 in adipose tissues.

AAV8-mediated Sirt1 gene transfer to the liver prevents high carbohydrate diet-induced nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease worldwide, and evidence suggests that it promotes insulin resistance and type 2 diabetes. Caloric restriction (CR) is the only available strategy for NAFLD treatment. The protein deacetylase Sirtuin1 (SIRT1), which is activated by CR, increases catabolic metabolism and decreases lipogenesis and inflammation, both involved in the development of NAFLD.

In vivo adeno-associated viral vector-mediated genetic engineering of white and brown adipose tissue in adult mice.

Adipose tissue is pivotal in the regulation of energy homeostasis through the balance of energy storage and expenditure and as an endocrine organ. An inadequate mass and/or alterations in the metabolic and endocrine functions of adipose tissue underlie the development of obesity, insulin resistance, and type 2 diabetes. To fully understand the metabolic and molecular mechanism(s) involved in adipose dysfunction, in vivo genetic modification of adipocytes holds great potential.

New insights into adipose tissue VEGF-A actions in the control of obesity and insulin resistance.

Vascular endothelial growth factor A (VEGF-A) is classically viewed as a key factor in angiogenesis and tissue remodeling. However, recent evidence suggests a potential role of this growth factor in the control of energy metabolism and adipose tissue function. In this regard, we and others have described the effects of the up and downregulation of VEGF-A in adipose tissue on the control of energy homeostasis.

Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance.

During the expansion of fat mass in obesity, vascularization of adipose tissue is insufficient to maintain tissue normoxia. Local hypoxia develops and may result in altered adipokine expression, proinflammatory macrophage recruitment, and insulin resistance. We investigated whether an increase in adipose tissue angiogenesis could protect against obesity-induced hypoxia and, consequently, insulin resistance.

Enforced expression of protein kinase C in skeletal muscle causes physical inactivity, fatty liver and insulin resistance in the brain.

Among the multitude of dysregulated signalling mechanisms that comprise insulin resistance in divergent organs, the primary events in the development of type 2 diabetes are not well established. As protein kinase C (PKC) activation is consistently present in skeletal muscle of obese and insulin resistant subjects, we generated a transgenic mouse model that overexpresses constitutively active PKC-beta(2) in skeletal muscle to test whether activation of PKC is sufficient to cause an aversive whole-body phenotype. Upon this genetic modification, increased serine phosphorylation in Irs1 was observed and followed by impaired (3)H-deoxy-glucose uptake and muscle glycogen content, and transgenic mice exhibited insulin and glucose intolerance as they age.

Expression of IGF-I in pancreatic islets prevents lymphocytic infiltration and protects mice from type 1 diabetes.

Type 1 diabetic patients are diagnosed when beta-cell destruction is almost complete. Reversal of type 1 diabetes will require beta-cell regeneration from islet cell precursors and prevention of recurring autoimmunity. IGF-I expression in beta-cells of streptozotocin (STZ)-treated transgenic mice regenerates the endocrine pancreas by increasing beta-cell replication and neogenesis.

Adipose overexpression of phosphoenolpyruvate carboxykinase leads to high susceptibility to diet-induced insulin resistance and obesity.

Obesity and insulin resistance are associated with increased serum free fatty acids (FFAs). Thus, a reduction in circulating FFAs may increase insulin sensitivity. This could be achieved by increasing FFA reesterification in adipose tissue.

Overexpression of c-myc in the liver prevents obesity and insulin resistance.

Alterations in hepatic glucose metabolism play a key role in the development of the hyperglycemia observed in type 2 diabetes. Because the transcription factor c-Myc induces hepatic glucose uptake and utilization and blocks gluconeogenesis, we examined whether hepatic overexpression of c-myc counteracts the insulin resistance induced by a high-fat diet. After 3 months on this diet, control mice became obese, hyperglycemic, and hyperinsulinemic, indicating that they had developed insulin resistance.

Overexpression of c-myc in diabetic mice restores altered expression of the transcription factor genes that regulate liver metabolism.

Overexpression of the c-Myc transcription factor in liver induces glucose uptake and utilization. Here we examined the effects of c- myc overexpression on the expression of hepatocyte-specific transcription factor genes which regulate the expression of genes controlling hepatic metabolism. At 4 months after streptozotocin (STZ) treatment, most diabetic control mice were highly hyperglycaemic and died, whereas in STZ-treated transgenic mice hyperglycaemia was markedly lower, the serum levels of beta-hydroxybutyrate, triacylglycerols and non-esterified fatty acids were normal, and they had greater viability in the absence of insulin.

Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance.

Adipose tissue glyceroneogenesis generates glycerol 3-phosphate, which could be used for fatty acid esterification during starvation. To determine whether increased glyceroneogenesis leads to increased fat mass and to explore the role of obesity in the development of insulin resistance, we overexpressed PEPCK, a regulatory enzyme of glyceroneogenesis in adipose tissue. Transgenic mice showed a chronic increase in PEPCK activity, which led to increased glyceroneogenesis, re-esterification of free fatty acids (FFAs), increased adipocyte size and fat mass, and higher body weight.