Coffee Diterpenes Have A Metformin-Like Anti-Diabetic Action

[Limon9]

My previous post highlighted the pathological mTOR-mediated aerobic glycolysis caused by endotoxin, so I thought it should be balanced with an example of glycolysis-boosting when oxidative phosphorylation is unimpaired. The experiment looked both in vitro and in vivo at the effects of kahweol, a diterpene compound found in unfiltered coffee. This molecule was found to be an activator of the AMP-activated protein kinase (AMPK), an enzyme which is associated with stimulating glucose uptake and fatty-acid oxidation, while suppressing fat synthesis. Kahweol reduced fat accumulation in cells and improved glucose clearance in live mice.

They inexplicably used a very high dose of kahweol in the mice, 100mg/kg every two days, when the typical cup of unfiltered coffee has 5-12 milligrams of the two major diterpenes, cafestol and kahweol. Some mouse studies used those physiological amounts of cafestol and saw benefits, so it's unlikely to be a freak-effect unique to kahweol megadoses.

AMPK is a target of fasting and popular birth-defect potions drugs like metformin, yet it is also activated by aspirin and methylene blue, and by mitochondrial uncoupling, on account of the increased ratio of AMP to ATP. (Longevity cultists as wannabe squirrel monkeys?). This is a good thread suggesting the effects of chronic AMPK activation on uncoupling and mitochondriogenesis, and how its activators can be considered "exercise mimetics", increasing endurance without training:

". . . Based on the present study it is unlikely that increasing lipid oxidation alone is sufficient to cause leanness. In view of the fact that increased FAO was considered one of the major mechanisms of AMPK in fat reduction and leanness, this leaves open the possibility that the adipose lowering effects of chronic AMPK activation are mediated via an alternate pathway such as increased mitochondrial biogenesis or increased expression of uncoupling proteins. [who saw that coming?]"

It is noted that in this study, acute AMPK activation is said to suppress glycogen synthase as well as fatty-acid-synthase, which might contribute to the seemingly inexplicable cases of insomnia or weakness caused by coffee or aspirin use you see on the forum.

Key Points
- Kahweol treatment in vitro prevented lipid accumulation in cells. This was determined to not be due to cytotoxicity.
- Kahweol treatment in vitro suppressed PPAR-gamma, C/EBPa, FABP and fatty acid synthase.
- Kahweol treatment in vitro activated AMPK.
- Anti-lipid-accumulation effect of kahweol was abolished by AMPK knockdown.
- Kahweol-treated mice (100mg/kg) had faster glucose clearance than vehicle-only (DMSO).

Kahweol inhibits lipid accumulation and induces Glucose-uptake through activation of AMP-activated protein kinase (AMPK)
BMB Rep. 2017 Nov;50(11):566-571. Baek J, Kim N, Song J, Chun K.

Highlights

"Pharmacotherapeutic drugs have been developed and used for treating obesity. According to meta-analysis about effects of anti-obesity drugs approved by the Food and Drug Administration (FDA), anti-obesity drugs promote moderate weight loss (2). Initially, the thyroid hormone [who saw that coming?] was selected as a therapeutic target, and Amphetamine became popular for an appetite suppressant in the late 1930s (3). Sibutramine was approved for long-term treatment in 1997. Orlistat was approved by the FDA for long-term treatment in 1999. It reduces intestinal fat absorption by inhibiting gastric and pancreatic lipases that hydrolyze triglyceride. The latest approved anti-obesity drugs were liraglutide and bupropion-naltrexone in 2014 (3)."

"However, safety concerns for anti-obesity drugs have emerged, and some drugs have been removed from the market. For example, dexfenfluramine, associated with cardiovascular side effects was withdrawn from FDA approval in 1997. Sibutramine also provokes severe cardiovascular events (5). Moreover, even with current drugs on the market such as orlistat, bupropion-naltrexone, phentermine-topiramate and liraglutide, treatment decisions are driven by co-existing medical conditions (6). For example, liraglutide may be a more relevant agent in individuals with type 2 diabetes because it lowers blood glucose levels. The use of bupropionnaltrexone in patients with alcohol or opioid dependence is associated with neuropsychiatric complications (7). Finally, the U.S. Drug Enforcement Administration (DEA) has classified most anti-obesity drugs as controlled substances, and many states have passed strict regulations relative to prescriptions and use."

"We established a screening method to determine lipid accumulation using 3T3-L1 cells. After screening with natural products, we identified kahweol, that is a diterpene found in beans of Coffea arabica and structurally related to cafestol (Fig. 1A and B). Recent research suggests that kahweol may have beneficial effects on bones by inhibiting osteoclast differentiation (11). Another recent study revealed that kahweol has anti-inflammatory and antiangiogenic effects (12), offering a possible mechanism for epidemiological studies revealing a relationship between unfiltered coffee intake and decreased risk of cancer. In this study, we examined kahweol’s effect on adipocyte differentiation and lipid accumulation. Because AMP-Activated Protein Kinase (AMPK) is an enzyme regulating glucose transport and lipid metabolism, AMPK is a therapeutic target of diabetic agent anti-and obesity (13). Interestingly, we determined that kahweol has a potent effect on activation of AMPK, thereby increasing glucose uptake in blood of sugar-taken mice. We suggest that kahweol may be an ideal agent for obesity attenuation and suggest clinical trials further examine potential applications."

"Lipid accumulation in 3T3-L1 cells was measured using Oil Red O staining on day 6 (Fig. 1C). Kahweol (25 mcg/ml) significantly reduced lipid accumulation, whereas cafestol did not reduce lipid accumulation (Figs. 1C and D). To confirm the inhibitory effect of kahweol on lipid accumulation is not a result of cell cytotoxicity, a cell viability assay was conducted. We confirmed there was no difference in cell viability (Fig. 1E). We tested if kahweol treatment affects protein expression of PPARg, C/EBPa, FABP4, and FASN, that regulate adipocyte differentiation and lipid metabolism. Kahweol significantly reduced expression of these proteins in a dose-dependent manner (Fig. 1F)."

"Many studies have reported that kahweol suppresses activation of AKT and ERK1/2 (11, 14). AKT and ERK1/2 pathways were reported to regulate adipocyte maturation (15). We examined changes in activation of these signaling pathways that are involved in adipocyte differentiation and lipid metabolism (Fig. 4A). Phosphorylation of AKT and JAK2 decreased after kahweol treatment; in contrast, phosphorylation of ERK1/2 was not affected by kahweol treatment. Interestingly, we found that kahweol treatment significantly increased the phosphorylation of AMPK and its downstream target Acetyl-CoA carboxylase (ACC). We also validated that kahweol treatment increased phosphorylated AMPK and ACC in a time-dependent manner (Fig. 4B). Many studies have reported that AMPK is activated by phosphorylation and that it inhibits adipocyte differentiation and increases glucose uptake and fatty acid oxidation (13)."

"The inhibitory effect of kahweol on lipid accumulation was alleviated by knockdown of AMPK using siRNAs (Fig. 4C). Knockdown of AMPK also reduced the effect of kahweol on expression of adipogenesis and lipid metabolism-related genes (Fig. 4D). These results suggest that kahweol suppresses lipid accumulation by up-regulation of AMPK activation. Activation of AMPK promotes cellular glucose uptake through glucose transporter. Metformin known as AMPK activator has an anti-diabetic effect (16). Since kahweol also has the effect of AMPK activation as metformin, we hypothesized that kahweol may reveal an anti-diabetic effect. In 3T3-L1 cells, kahweol treatment elevated glucose uptake in a dose-dependent manner (Fig. 4E). In addition, we tested if kahweol may improve glucose homeostasis in vivo. 8 week-old mice were administered kahweol every 2 days by oral gavage. After 2 weeks, we conducted glucose tolerance test (GTT). Clearance of blood glucose was faster in kahweol-treated mice than in control mice (Fig. 4F)."

". . . we determined that kahweol induces activation of AMPK. AMPK is a serine/threonine kinase, that is a key enzyme for maintaining cellular energy homeostasis (13, 26). AMPK has a heterotrimer complex consisting a, b and g subunits. Catalytic a subunit contains Thr172 phosphorylated by AMPK upstream kinase. Regulatory g subunit has four Cystathionine b synthase (CBS) domains that create two AMP binding sites known as the Bateman domain. One of major roles of AMPK is the regulation of lipid metabolism. AMPK activation phosphorylates and inactivates acetyl-CoA carboxylase, an enzyme involved in fatty acid synthesis, and consequently inhibits synthesis of fatty acid and increases B-oxidation. AMPK also regulates glucose metabolism. AMPK increases glycolysis by activating of 6-phosphofructo-2-kinase/ fructose-2, 6-bisphosphatase 2/3 and suppresses glycogen synthesis through inhibition of glycogen synthase (13). AMPK increases glucose uptake by promoting glucose transporter 4 and hexokinase 2 expressions in skeletal muscle cells (27, 28). AMPK modulates various metabolic processes and its dysregulation is commonly observed in type 2 diabetes, obesity, and several types of cancer."

"In this study, kahweol induces phosphorylation of AMPK. The effect of kahweol treatment on reducing lipid accumulation was decreased by depletion of AMPK, suggesting that the inhibitory effect of kahweol on lipid accumulation was due to phosphorylation of AMPK. Mice were fasted for 15 hours and then fed glucose. The blood glucose level of kahweol-pretreated mice decreased faster than untreated mice. However, we do not know how kahweol increases phosphorylation of AMPK."

 

[LadyRae]

Really interesting, thanks! What is meant by "unfiltered"?
Would a French press be better than drip? I don't use a paper liner in my drip machine, just the metal screen in the basket ..

I love a French press, but I get lazy as I drink a lot of coffee...

 

[Limon9]

Really interesting, thanks! What is meant by "unfiltered"?
Would a French press be better than drip? I don't use a paper liner in my drip machine, just the metal screen in the basket ..

I love a French press, but I get lazy as I drink a lot of coffee...

Yeah, I mean non-paper-filtered. I basically just rotate between chemex, French press and . . . instant, depending on mood/consumption.

 

[LadyRae]

Yeah, I mean non-paper-filtered. I basically just rotate between chemex, French press and . . . instant, depending on mood/consumption.

Sounds good, coffee on!