Ursolic acid, a lipophilic pentacyclic triterpenoid, is found in the waxy coats of apples, other fruits, and various herbs. Recent research suggests that ursolic acid may offer several health benefits, including potential support for weight loss. This article explores the science behind these claims, examining how ursolic acid might influence body composition and metabolism.
Ursolic Acid and Muscle Health
Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance, and fatty liver disease. Studies have shown that ursolic acid can increase skeletal muscle Akt activity and stimulate muscle growth. For example, research involving mice on a high-fat diet demonstrated that ursolic acid increased Akt activity in skeletal muscle, along with downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa), and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength, and exercise capacity.
Muscle Atrophy Inhibition
Ursolic acid was identified in a screen for small molecule inhibitors of skeletal muscle atrophy. Researchers determined the effects of fasting and spinal cord injury on skeletal muscle mRNA levels in humans and used that information to generate unbiased mRNA expression signatures of human skeletal muscle atrophy. They then used these signatures to query the Connectivity Map for compounds whose expression signatures negatively correlated with the signatures of human muscle atrophy. Ursolic acid was the only compound with an mRNA expression profile that showed a statistically significant negative correlation with the profiles of both the fasting and the spinal cord injury models of atrophy. The authors then showed that ursolic acid increased muscle mass by 7% in fasting mice. Ursolic acid was also effective in mice with denervation-induced hindlimb atrophy.
Ursolic acid decreased the activity of the catabolic genes MuRF-1 and Atrogin-1 in muscle cells, which are known as two of the most potent genes associated with catabolic (muscle-breakdown) activity. Also, ursolic acid was shown to increase the activity of the Insulin-like growth factor-1 (IGF-1) gene and IGF-1 blood level concentrations. The protein kinase Akt (also known as PKB) inhibits muscle atrophy and promotes muscle hypertrophy.
Ursolic Acid and Brown Fat
Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Brown fat is thermogenic, meaning it burns calories to generate heat. This increase in brown fat contributes to increased energy expenditure. Ursolic acid reduced interscapular white fat, consistent with its effects on epididymal and retroperitoneal white fat. In contrast, ursolic acid increased interscapular brown fat. As an additional test, expression of uncoupling protein 1 (UCP1), a brown fat marker, was measured, and it was found that ursolic acid increased UCP1. Ursolic acid-treated mice were more resistant to hypothermia.
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Ursolic Acid, Energy Expenditure, and Obesity
Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance, and decreased hepatic steatosis. Studies using mice fed a high-fat diet supplemented with ursolic acid showed promising results. These mice gained less weight and had smaller epididymal and retroperitoneal fat pads, indicating a reduction in obesity. Chronic treatment with ursolic acid significantly increased energy expenditure during both dark and light cycles without significantly altering spontaneous activity. These data indicated that ursolic acid reduced obesity by increasing resting energy expenditure.
Impact on Glucose and Liver Health
In addition to reducing obesity, ursolic acid also improved glucose homeostasis. Fasting blood glucose levels were normalized in ursolic acid-treated mice, and glycemic excursion during a glucose tolerance test was reduced. Ursolic acid also reduced liver weight, hepatocellular steatosis, and hepatic triglyceride content, indicating reduced fatty liver disease. Furthermore, it reduced plasma aminotransferases, suggesting reduced hepatocyte injury. At the molecular level, ursolic acid reduced the steady-state level of Srebpf1 mRNA, which encodes SREBP-1c, a transcription factor that promotes lipogenesis and fatty liver disease. Accordingly, ursolic acid reduced expression of three key SREBP-1 target genes (acetyl-CoA carboxylase 1 (Acaca), fatty acid synthase (Fasn) and stearoyl Co-A desaturase-1 (Scd1)), and it markedly reduced the level of acetyl-CoA carboxylase 1 (ACC) protein.
Ursolic Acid and Gut Microbiota
Ursolic acid intervention could change the ratio of the thick-walled phylum to the anaplasma phylum at the portal level and increase the genera Lactobacillus, Anaplasma, and Ackermannia. In addition, metabolomics analyses showed that the beneficial effects of UA on obesity were partially dependent on amino acid metabolism.
Study Details and Findings
To investigate the effects of ursolic acid in diet-induced obese mice, 8-week-old male C57BL/6 mice were provided ad libitum access to a high fat diet or a high fat diet supplemented with 0.14% ursolic acid for 6 weeks. This high fat diet (55% calories from fat) is known to cause obesity, as well as glucose intolerance and fatty liver disease. After 6 weeks on these diets, triceps muscle was harvested and steady-state Akt phosphorylation, a marker of Akt activity, was examined. Ursolic acid increased Akt phosphorylation more than two-fold.
Quadriceps mRNA levels were determined using qualitative real-time RT-PCR (qPCR). Levels in UA-treated mice were normalized to the average levels in mice fed HFD lacking ursolic acid, which were set at 1. Ursolic acid increased both Hk2 and Vegfa mRNAs. Local Igf1 expression is an autocrine/paracrine mechanism that increases skeletal muscle IGF-I/Akt signaling and thus muscle growth. Ursolic acid's effects on skeletal muscle Igf1 mRNA in high fat-fed mice were examined, and it was found that ursolic acid increased it. Ursolic acid increased grip strength and skeletal muscle weight. Ursolic acid also increased the size of both fast and slow skeletal muscle fibers without altering the ratio of fast to slow fibers. Ursolic acid-treated mice ran significantly farther than control mice. Ursolic acid did not alter blood pressure, and it induced a slight but significant reduction in resting heart rate.
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Sources of Ursolic Acid
Ursolic acid is contained in many edible fruits and herbs. It contributes to the waxy coats on apples, other fruits, and many herbs, including some folkloric herbal medicines for diabetes.
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