Raspberry Ketone

1.1. Sources

Raspberry ketone (also known as 4-(4-hydroxyphenyl) butan-2-one) is a compound extracted from red raspberries that is usually used as a scenting and flavoring agent in foods and cosmetics.^[2].

It is found naturally in many foods, most notably raspberries (in which case it is synthesized from coumaroyl-CoA) but also in Rheum officinale.^[3] Most raspberry ketone used commercially is synthesized^[4] or produced via bacteria^[5][6], however, due to its high demand in cosmetics and as a flavoring agent. It has been estimated that dietary intake for an average human is around 0.42mg/kg bodyweight,^[7] mostly consumed through processed foods which have raspberry ketone added as a flavoring agent.

1.2. Structure

Raspberry ketone has a vaguely similar structure to Synephrine and Ephedrine, where the butanone-substituted phenyl group of raspberry ketone replaces ethylamine group of synephrine or ephedrine. There is also some structural similarity to capsaicin, with para-substituted phenolic and ketone functional groups in common.^[8]

2.1. Metabolism

After oral ingestion, raspberry ketone is targeted for sulfation and glucuronidation and is also metabolized by the hepatic P450 enzyme system in animal models.^[9]

Raspberry ketone (4-(4-hydroxylphenyl)butan-2-one) can be metabolized via ring conjugation (resulting in 4-(4-hydroxylphenyl)butan-1,2-diol) or via side-chain oxidation (resulting in 4-(4-hydroxylphenyl)butan-2,3-diol).^[9] Raspberry ketone and its aforementioned oxidized metabolites are excreted in urine, sometimes conjugated to either sulphate or glucuronide.^[9]

3.1. Mechanisms

There is mixed evidence as to whether raspberry ketone can stimulate lipolysis. One study in an adipocyte cell culture model (3T3-L1 adipocytes) noted that 10µM of the compound tripled glycerol release, an indicator of lipolysis.^[8] A later, more comprehensive study in the same 3T3-L1 adipocyte cell line found that 10µM raspberry ketone increased the activation of several genes involved in lipolysis, including adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL).^[10]

In contrast, studies on the effects of raspberry ketone on lipolysis in primary cells are not consistent with those in adipocyte cell lines. Primary cells obtained from animal tissue are often better suited to model in vivo processes than continous cell lines such as 3T3-L1 adipocytes, which can have substantial genetic drift from being kept in continuous culture. A study using primary fat cells from a rodent model failed to show any lipolysis-stimulating effects with raspberry ketone alone. This study did note that concentrations in the range of 1-10mM stimulated lipolysis in the presence of norepinephrine, however, suggesting that raspberry ketone may augment norepinephrine- mediated lipolysis^[11] in primary adipocytes. There is no detectable binding of raspberry ketone to β-adrenergic receptors,^[11] and more research is needed to examine whether raspberry ketone augments norepinephrine- mediated lipolysis in vivo.

Increased secretion and cellular levels of adiponectin were also noted after 4 days of incubating fat cells with raspberry ketone.^[8] It has been noted to be protective against steatohepatitis in a rat model while also attenuating a rise in leptin levels.^[12]

Although raspberry ketone is a potent stimulator of lipolysis and lipolytic gene expression in the 3T3-L1 adipocyte cell line, studies in primary adipocytes have failed to show an effect. Raspberry ketone has been shown to augment norepinephrine-induced lipolysis in primary adipocytes, however. More studies are needed to assess whether this occurs in vivo.

Raspberry ketone has also been shown to suppress adipocyte differentiation (i.e. the transformation of precursor cells in to adipocytes) and fat accumulation in 3T3-L1 adipocytes by downregulating adipogenic gene expression including PPARγ and C/EBPα.^[10]

Rats fed 0.5-2% raspberry ketone (bringing the total daily intake to 0.545-2.18g/kg) during periods of high fat overfeeding noted dose-dependent anti-obesity actions in preventing body weight gain, although the group fed 2% raspberry ketones still gained more weight than the control group fed a normal diet.^[11]

Toxicological studies also noted decreases in body weight associated with raspberry ketones at 1% of the diet.^[7]

3.2. Interventions

The one human study to investigate the effects of raspberry ketone found a fat loss of 7.8% relative to the 2.8% in placebo, and weight loss of 2% relative to 0.5% in placebo, without detectable differences in caloric intake. This study was highly confounded, however, as raspberry ketone was co-administered with several other supplements in a "METABO" formulation (raspberry ketone paired with caffeine, capsaicin, garlic, ginger and Citrus aurantium as a source of synephrine), so the benefits cannot be traced back to raspberry ketone per se.^[1] This study also noted an elevation of serum leptin (but no influence on resistin nor adiponectin) associated with intervention.^[1]

Human evidence for the efficacy of raspberry ketones in promoting fat loss is highly confounded. There is no evidence to support the idea that raspberry ketone in isolation can induce fat loss.

4.1. Testosterone

In vitro studies with breast cancer cell lines suggest that raspberry ketone can inhibit the androgen receptor, with an IC₅₀ value of 252uM.^[13]

Rasberry ketone can block the androgen receptor, but this occurs at high concentrations that may not be physiologically relevant. Oral ingestion of standard (low) doses is unlikely to affect androgen receptor signaling.

5.1. Liver

A study conducted in rats noted that 1-2% of the diet as raspberry ketone was able to attenuate increases in liver fat associated with a high fat overfeeding diet, with the 2% group not being significantly different than control (control at 10.7+/-1.6mg/g triglycerides in the liver, high fat control at 35.6+/-6.8mg/g, and 2% raspberry ketone at 17.9+/-1.9mg/g).^[11] These doses were later tested in another rat model of steatohepatitis,^[12] and decreases in liver triglycerides and cholesterol were noted with normalization of serum HDL-C and LDL-C. Liver enzymes were beneficially influenced, although to a minor degree.^[12]

It is thought that this is due to a preservation of PPARα and LDL receptors in the livers of rats fed both raspberry ketone and an obesogenic diet.^[12]

Rat studies suggest that raspberry ketone may have beneficial effects on liver fat buildup, but there is no evidence to support this effect in humans. Impractically high doses of raspberry ketone were used to achieve these effects in rats.

Raspberry ketone may have some beneficial influences on liver fat buildup, although this has only been tested in rat models, and may not be true in humans. Also, high, impractical doses of raspberry ketone were used to acheive these effects.

6.1. Hair

Raspberry ketone, used topically as a 0.01% solution applied once daily for 5 months, has been found to increase IGF-1 production in the dermis (skin) and may lead to increased hair growth.^[14] These effects seem to be mediated through vanilloid-receptor 1 (VR1) activation, similar to capsaicin, a compound with a similar structure but a longer tail.

6.2. Skin

Raspberry ketone has also been linked to increased skin elasticity when administered topically as a solution of 0.01% in human females.^[14]

Raspberry leaf tea is a herbal medicine traditionally recommended to pregnant women, and contains various compounds such as 'gallo- and ellagitannins, flavonoids, vitamin C, various alcohols, aldehydes, ketones, organic acids, terpenoids, carbohydrates, and glycosides'.^[15] The ketones this list refers to are the raspberry ketones, most notably 4-(4-hydroxyphenyl)butan-2-one.

7.1. Interactions with pregnancy

Raspberry leaf tea is often recommended to pregnant women to shorten labor^[16][17] The mechanism of this is not yet elucidated, but does not appear to be mediated by uterine contractility.^[18]

Adverse effects are not usually seen at dosages of 1.2-2.4g raspberry leaf daily, but neither are statistically significant benefits on labour length.^[19][15][17]

In regards to safety during pregnancy, a recent review suggested that not enough information exists to draw a conclusion due to small sample sizes.^[15]

There is not much evidence on the safety threshold for raspberry ketone in humans due to its relatively new status as a supplement.

Fat cells show no cytotoxicity, however, at doses up to five times (100μM) the effective dose noted above.^[8] In rats, intake of up to 100mg/kg bodyweight does not cause any short-term alterations in markers of blood health^[7], and the LD⁵⁰ is established at around 1.3-1.4g/kg bodyweight.^[7]