AKT2
RAC-beta serine/threonine-protein kinase (EC 2.7.11.1) (Protein kinase Akt-2) (Protein kinase B beta) (PKB beta) (RAC-PK-beta)
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Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. Despite frequent occurrence of these disorders, the genetic pathways influencing UA metabolism and the association with disease remain poorly understood. In humans, elevated UA levels resulted from the loss of the of the urate oxidase (Uro) gene around 15 million years ago. Therefore, we established a Drosophila melanogaster model with reduced expression of the orthologous Uro gene to study the pathogenesis arising from elevated UA. Reduced Uro expression in Drosophila resulted in elevated UA levels, accumulation of concretions in the excretory system, and shortening of lifespan when reared on diets containing high levels of yeast extract. Furthermore, high levels of dietary purines, but not protein or sugar, were sufficient to produce the same effects of shortened lifespan and concretion formation in the Drosophila model. The insulin-like signaling (ILS) pathway has been shown to respond to changes in nutrient status in several species. We observed that genetic suppression of ILS genes reduced both UA levels and concretion load in flies fed high levels of yeast extract. Further support for the role of the ILS pathway in modulating UA metabolism stems from a human candidate gene study identifying SNPs in the ILS genes AKT2 and FOXO3 being associated with serum UA levels or gout. Additionally, inhibition of the NADPH oxidase (NOX) gene rescued the reduced lifespan and concretion phenotypes in Uro knockdown flies. Thus, components of the ILS pathway and the downstream protein NOX represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones, as well as extending human healthspan.
MeSH Terms
- Animals
- Animals, Genetically Modified
- Cohort Studies
- Disease Models, Animal
- Drosophila melanogaster
- Feeding Behavior
- Female
- Gene Knockdown Techniques
- Gout
- Humans
- Insulin
- Kidney Calculi
- Longevity
- Male
- Metabolic Networks and Pathways
- Middle Aged
- NADPH Oxidases
- Polymorphism, Single Nucleotide
- Purines
- Signal Transduction
- Urate Oxidase
- Uric Acid
Aging, obesity and sedentarism are among the most important predictors of cardiometabolic diseases. Aiming to reduce the impact of the combination of these three factors, we tested the therapeutic and preventive effects of exercise in aging and obese rats on the following cardiometabolic disease risk parameters: body fat, blood pressure, blood lipids, and glycemic homeostasis. Eighteen male Wistar rats (initial age = 4 months, and final age = 14 months) were randomly distributed into three aging and obese groups: sedentary, therapeutic exercise and preventive exercise. Food and caloric intake, body adiposity, muscle mass, cardiovascular parameters, biochemical markers, glycemic homeostasis, and gene expression of insulin-dependent, insulin-independent and insulin resistance pathways in skeletal muscle were evaluated. Therapeutic and preventive exercises were associated with higher food and caloric intake, and expression of TBC1D1 in the soleus muscle, as well as lower total cholesterol/HDL and LDL/HDL ratios, glucose levels at the end (90 min) of the glucose tolerance test and IKBKB expression in the gastrocnemius and soleus muscles. Only the preventive exercise improved the cardiovascular and body composition parameters, glucose tolerance, insulin resistance and insulin sensitivity, besides reducing total cholesterol, triglycerides, triglycerides/HDL ratio, plasmatic insulin and MAPK8 expression in soleus. The preventive exercise group also presented greater expression of INRS, IRS1, IRS2, PIK3CA, AKT1, and SLC2A4 in gastrocnemius and soleus, TBC1D1 in gastrocnemius, and AKT2 and PRKAA1 in soleus. Therapeutic exercise promoted some improvements on cardiometabolic parameters in aging and obese rats, however, the best benefits were achieved through the preventive exercise.
MeSH Terms
- AMP-Activated Protein Kinases
- Adipose Tissue
- Adiposity
- Aging
- Animals
- Blood Glucose
- Blood Pressure
- Body Composition
- Cardiovascular Diseases
- Cholesterol
- Disease Models, Animal
- Exercise Therapy
- Glucose Tolerance Test
- Homeostasis
- Insulin
- Insulin Resistance
- Lipids
- Lipoproteins, HDL
- Male
- Metabolic Diseases
- Mitogen-Activated Protein Kinase 8
- Muscle, Skeletal
- Obesity
- Physical Conditioning, Animal
- Proteins
- Proto-Oncogene Proteins c-akt
- Rats
- Rats, Wistar
- Triglycerides
Keywords
- Aerobic exercise
- Aging
- Insulin resistance
- Metabolic Diseases
- Obesity