A recent study on the effects of the flavone 7,8-dihydroxyflavone on mice discovered something rather surprising; that it limited weight gain in mice fed a high-fat diet – but only in female mice. 
The effects of the small molecule 7,8-dihydroxyflavone (henceforth referred to as 7,8-DHF) derive from its pharmacological similarities to brain-derived neurotrophic factor (BDNF), a protein that helps the brain to maintain a healthy supply of neurons. Like BDNF, 7,8-DHF is a potent agonist of the tyrosine kinase receptor B (TrkB), and to date most of the research on 7,8-DHF has focused on the effects of TrkB signalling on cognitive function and neurogenesis in the brain. [For more information the reader is referred to Examine.com’s comprehensive summary of the research – link]
Unusually, the recent study examined the metabolic effects of 7,8-DHF, which – unexpectedly – they found were due to TrkB signalling in peripheral tissues, outside of the CNS. Earlier research by disparate groups had identified BDNF/TrkB signalling as a potential target in treating obesity, with several studies identifying an anorexic [appetite-suppressing] effect of exogenously administered [injected] BDNF. 7,8-DHF had already been identified as an orally-bioavailable BDNF mimetic [TrkB agonist], so in this study mice were treated with 7,8-DHF orally [via their drinking water], and the effects on their weight gain on either a standard chow or high-fat diet were observed. The unanticipated result was that only female mice treated with 7,8-DHF showed reduced weight gain from a high-fat diet. This triggered a series of further experiments in female mice to attempt to elucidate the mechanism(s) behind the anti-obesity effect observed.
- “7,8-DHF administration did not cause significant toxicity or undesirable side effects”
- “7,8-DHF treatment mitigates obesity-induced insulin resistance [in female mice]”
Unlike in previous experiments where BDNF had been administered directly to the brain, resulting in reduced food intake in test animals, oral 7,8-DHF actually caused an increase in food intake, which suggested that a) the reduction in body weight in 7,8-DHF treated mice wasn’t down to hypothalamic TrkB activation hampering the appetite, as might have been expected, and b) was instead down to an increase in the metabolism of the animals.
A comparison of the gene expression of treated and untreated animals identified a significant increase in the expression of uncoupling protein 1 (UCP1, also known as “thermogenin”) in the muscle cells of treated mice. UCP1 is the thermogenic (heat-producing) protein found in brown (and beige/brite) fat cells [See also: What is BAIBA?]. The researchers believe this increase in UCP1 is responsible for the anti-obesity effects observed in the female mice.
- “…UCP1 overexpression in skeletal muscle increases systemic energy expenditure and lipid utilization, leading to a reduction in gain of body weight of mice under HFD [high-fat diet] feeding.”
7,8-DHF- and high-fat diet-treated mice also experienced a significant increase in AMP-activated protein kinase (AMPK) phosphorylation in muscle tissue, which they believe is due to the reduction in cellular ATP caused by the enhanced UCP1 induction. AMPK is a regulator of lipid and glucose metabolism; AMPK activation increases fatty acid oxidation, contributing to the reduced body weight gain observed in the test animals.
- “Activation of the TrkB signalling in muscle leads to the expression of UCP1.”
- “Enhanced UCP1 is the key mechanism for the beneficial action of BDNF/TrkB signalling in muscular energy metabolism.”
Much has been made in the media of the fact that these effects were only seen in female mice, leading to suggestions that these effects may be replicable in female humans [e.g. “Women May Benefit from New Weight Control Agent that Works in Mice”]. However, differences in response between the sexes to BDNF are, as the researchers themselves point out, commonly observed in mice – but aren’t necessarily going to be repeated in humans. Whether 7,8-DHF will limit weight gain or aid fat loss in either – or neither – gender in humans remains to be seen.
1. Chan CB, Tse MCL, Liu X, Zhang S, Schmidt R, Otten R, et al. Activation of Muscular TrkB by its Small Molecular Agonist 7,8-Dihydroxyflavone Sex-Dependently Regulates Energy Metabolism in Diet-Induced Obese Mice. Chemistry & Biology (2015). http://dx.doi.org/10.1016/j.chembiol.2015.02.003
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