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   Dec 01

Herbal Berberine Boosts Brown Fat Activity

The naturally occurring plant alkaloid berberine, used in many Chinese herbal medicines, was found to increase energy expenditures in rodents by increasing brown fat activity.

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The naturally occurring plant alkaloid berberine was found to increase energy expenditures in rodents by increasing brown fat activity in mice.

This discovery has fueled speculation that the pharmacologic enhancement of brown adipose tissue development and activity could be a useful strategy for treating obesity.

Genetically obese mice injected daily with the compound for 4 weeks showed evidence of increased energy expenditures, and they also generated more heat when exposed to cold, reported Guang Ning of the Shanghai Institute of Endocrine and Metabolic Disease in Shanghai, and colleagues.

Berberine (BBR) administration was found to limit weight gain, improve cold tolerance, and enhance brown adipose tissue (BAT) activity in obese db/db mice, and the alkaloid was found to induce the development of brown-like adipocytes in inguinal, but not epididymal, adipose deposits, they wrote in Nature Communications.

“The beneficial effects of berberine on metabolic improvement have evoked a substantial interest in the compound as a potential treatment for obesity and diseases such as diabetes,” the researchers wrote. “Our data support a clear function of berberine in regulating energy expenditure by initiating a thermogenic program.”

Berberine Has Metabolic Effects

Recent studies have revealed that, in addition to rodents and newborn humans, adult humans have functional BAT, which is composed of single chambered lipid droplets and large numbers of mitochondria that contain uncoupling protein-1 (UPC1).

This discovery has fueled speculation that the pharmacologic enhancement of BAT development and activity could be a useful strategy for treating obesity, the researchers noted.

Berberine has traditionally been used as an anti-diarrhea agent in Chinese herbal medicine, but it has recently been found to have metabolic effects, the researchers wrote.

The authors examined the metabolic effects of berberine by administering the compound to genetically engineered db/db obese mice for 4 weeks. During treatment the mice were protected from weight gain and berberine appeared to be well tolerated.

Other tests showed that berberine ameliorated glucose tolerance.

“Our results demonstrate that BBR reduced body weight and improved disordered metabolic profiles,” the researchers wrote. “The rectal temperatures of BBR-treated animals were significantly higher than that in the vehicle group, which means that the mice in BBR group could generate more heat during resting periods.”

BBR Helps Body Adapt to Cold

Another set of experiments conducted by the investigators demonstrated that BBR increased energy expenditure and adaptive thermogenesis in both db/db mice and normal, wild-type mice fed high-fat diets.

The researchers analyzed the actions of berberine using a comprehensive lab animal monitoring system (CLAMS). When normalized to their lean mass, berberine-treated mice showed higher oxygen consumption and carbon dioxide production rates through a 12-hour light/dark cycle compared with control (wild type) animals. db/db mice treated with berberine showed significant increases in the whole-body energy expenditure.

The increase in energy expenditure in the berberine-treated mice was not found to be due to an increase in physical activity. Respiratory exchange ratio (RER) decreased significantly upon berberine treatment, demonstrating that berberine can shift the fuel preference towards fatty acids, the researchers noted.

To further examine the differences in energy expenditures, the researchers performed a cold tolerance test to gauge adaptive thermogenesis, another major component of energy expenditure. During 2 hours of exposure to cold, body temperatures of the nontreated db/db mice dropped significantly, displaying impaired thermogenesis compared with the berberine group.

“This result shows that BBR was able to increase body adaptation to cold exposure by generating more heat,” the researchers wrote.

BBR Activated Key Genes

BAT is a major tissue where energy is produced into the form of heat to maintain the body temperature. Active BAT can be identified in human adults by FDG-PET/CT scans.

The researchers used 18F-FDG with a micro PET/CT that can be used in rodents to characterize the activity of berberine-treated BAT in vivo.

The combination of CT and PET images clearly showed that the PET signal was more highly detected in the interscapular position of the berberine-treated mice. The calculation results of the standard uptake values showed that berberine had a greater capacity to increase the activity of BAT in drug-treated mice.

Consistent with the reduction in body weight, the db/db mice had smaller brown adipocytes with berberine treatment, and they accumulated substantially less lipids in the brown fat. The number of mitochondria was increased as observed by means of transmission electronic microscopy after berberine treatment.

Berberine treatment induced the activation of a network of genes controlling energy expenditure and thermogenic program in BAT. The expression of several transcription factors, including PGC-1-alpha, estrogen-related receptor-alpha and nuclear respiratory factor 1, was strongly activated in the BAT of berberine-treated mice.

The expression of the UCP1 and other classical BAT marker genes, such as CIDEA, COX8b and lsdp5, were strongly induced, and the expression of genes controlling fatty acid oxidation and components of the mitochondrial electron transport chain were also enhanced.

Western blot analysis indicated that UCP1, PGC-1-alpha, phosphorylation of AMPK, and other important proteins expression were enhanced by berberine treatment.

When fractionated and differentiated primary BAT adipocytes were treated with berberine and the patterns of thermogenic gene expression were assessed, “messenger RNA and protein expression of known BAT markers were robustly increased to a high level in the BBR-treated group,” the researchers wrote, suggesting that berberine could function as an activator of thermogenic programming and increase the activity of BAT.

Increased Browning

The series of studies also demonstrated that berberine regulates UCP1 transcription through AMPK/PGC-1-alpha.

To elucidate the mechanism of increased browning in inguinal white adipose tissue and UCP1 activation, the researchers used differentiated multi-potent C3H10T1/2 adipocytes as a cell model. When they stained differentiated C3H10T1/2 adipocytes with UCP1 antibody they noted strong staining in the cytoplasm of the berberine group, which was further verified by immunoblotting.

When they stained adipocytes with a red fluorescent dye that stains mitochondrial mass, known as Mito-Tracker Red, they found significantly strong Red stain in the cytoplasm of berberine-treated cells.

These and similar investigations suggested that berberine activates AMPK and recruits PGC-1-alpha to the UCP1 promoter, inducing UCP1 expression.

The series of experiments also revealed that AMPK in the ventromedial nucleus of the hypothalamus (VMH) is not necessary for berberine’s effect on the thermogenic program and body weight.

“We have demonstrated BBR could regulate a thermogenesis program in both BAT and [white adipose tissues], and these effects are AMPK/PGC-1-alpha dependent,” the researchers wrote. “Our data establish BBR as having a previously unrecognized role in increasing energy expenditure, which might have a therapeutic role in the treatment of obesity.”

The researchers noted that it is possible VMH AMPK is not involved in berberine’s thermogenic effect because berberine showed robust induction in thermogenic program in primary brown and white adipocytes in their experiments.

“However, we could not exclude the possibility that another nuclei of hypothalamus, such as arcuate, or another part of brain, participated in the thermogenic program induced by BBR, which needs to be studied further,” Ning and colleagues wrote.

“Combined with our work, BBR could activate and expand the thermogenic machinery in vivo to provide a robust defense against obesity. We reveal the molecular target and mechanism by which BBR potently regulated the transcription of UCP1 in brown and white adipocytes through AMPK activation and PGC-1-alpha recruitment. These findings establish an important role for BBR in regulating adipose tissue thermogenesis and white adipose plasticity towards BAT, and we identify BBR as a new potential drug for treating patients with obesity.”

The study was funded by the National Natural Science Foundation, the Shanghai Municipal Education Commission, and the Shanghai Education Development.

The researchers disclosed no relevant relationships with industry.

Primary source: Nature Communications
Source reference: Zhang Z, et al “Berberine activates thermogenesis in white and brown adipose tissue” Nature Comm 2014; DOI: 10.1038/ncomms6493.

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