Campari is a dual bile acid receptor agonist that activates AMPK

I am a huge fan of Italian bitter liqueurs.  I was first introduced to the idea when I was working at Memorial Sloan-Kettering in Manhattan.  A co-worker brought in a six pack of bitter soda from a local pizza place.  I took a sip.  It was revolting.  My only thought was, “this tastes like bile!  Literally dry heaves.”

It was weird, though, the sweet and tart balanced out the bitter somehow.  I took another sip.  Still very odd, but somehow I enjoyed it?

Fast forward 20 years and I have developed a love of Italian Amaro.  The most well known (in the US) of which is Campari.  I delight in initiating new members of the Campari club.  The conversation goes something like this.

“Have you ever had Campari?”

“No.  What is it?”

“It’s an Italian bitter liqueur.  It tastes like bile.”

“Like bile?!”

“Yeah, literally like dry heaves but sweet and nice somehow.”

Somehow I usually get them to try it.  Most people drink Campari in a cocktail such as a negroni but I just drink it straight at room temperature.  Reactions to it…  vary.

A Medicinal Liqueur

Italians have been making Amaro since Greek and Roman times.  A legend is that Pliny the elder, who died in 79 AD, made amari.  After that, monks took up the tradition of making regional Amari. Amari is the plural.

Since the beginning, Amaro has been considered a health drink.  It is made from grape brandy with a neutral flavor that is steeped with botanicals which can include gentian root, citrus peel, wormwood, rhubarb root, aloe, mugwort, cinnamon, and hundreds of others.

European alchemists remain persuaded that elixirs had beneficial qualities and, in particular, could prolong life—a belief they shared, or perhaps imported from Chinese culture. 

Amari” , Carla Passino, Italy Magazine.

Hundreds of years ago, our ancestors sipped liqueurs to strengthen their constitution. “They thought multiple sips a day kept any ailments away,” says Vance Henderson, brand ambassador for Drambuie.   …  According to legend, Henry IV, the king at that time in 1605, sent a representative to their monastery in Vauvert to deliver the directions for making the “elixir of long life.” 

The Medicinal Roots of Modern Liqueurs”, Meredith Bethune, Mar 22, 2017

Bitter Amari are often taken before a meal as an aperitif or after a meal as a digestif.  This is said to stimulate bile production and aid in digestion.  

Bile Acid Receptors and AMPK

The monks may have been onto something.  In recent posts I’ve talked about the molecular sequence of events leading from consumption of linoleic acid to a torpid metabolism and that the best way to escape the torpid metabolism might be to stimulate AMPK.  

There are two bile acid receptors, known as tgr5 and FXR.  

Tgr5 is expressed on the cell surface and when it  is activated by certain specific bile acids, it activates adenylate cyclase which creates cAMP, which activates AMPK​1​.  Tgr5 is expressed in most tissues, including liver, the small and large intestine, the brain and the adrenal glands.

Tgr5 also causes GLP-1 to be released into the bloodstream.  GLP-1 is a circulating hormone that … wait for it … activates AMPK​2​.

FXR is yet another member of the nuclear receptor superfamily, just like PPARy and the aryl hydrocarbon receptor (AhR).  In a recent article I explained that members of the “superfamily” are transcription factors (they turn other genes on) that form dimers (they bind to another family member) before they can do their job.  It takes two to tango.  

SREBP-1c and LXR are members of the superfamily who form a dimer to increase the expression of lipogenic (fat making) genes.  AMPK phosphorylates SREBP-1c and turns it off.

When FXR is activated it increases the expression of SHP​3​, which binds to LXR and blocks it.  Without a binding partner, SREBP-1c can’t increase the expression of lipogenic genes, including SCD1Low levels of SCD1 increase activation of AMPK.

So the bile acid receptors are coordinating to increase AMPK activation.  Tgr5 is increasing the activity of AMPK directly, but also indirectly via the release of GLP-1.  AMPK and FXR are coordinating to turn off lipogenic gene expression, including SCD1, both through AMPK phosphorylation of SREBP-1c and by FXR increasing expression of SHP, which competes with SREBP-1c for LXR.  Low levels of SCD1 increase activation of AMPK.

Campari tastes like bile

The reason that the Amari have a bitter taste, like bile, is that the body sees the bitter polyphenols as bile.

Gentian is known as the king of bitter herbs and it is the most common bittering agent in Amari.  The bitterness of gentian is caused by a polyphenol called gentiopicroside.  Gentiopicroside is a tgr5 agonist (turns it on)​4​.  Gentiopicroside has been shown to prevent obesity in a diet induced obese rodent model.​5​

The second major component of Amari is citrus.

Without citrus to relieve the tension between bitter and sweet an amaro just doesn’t have all the notes it needs.

The 14 Most Popular Herbs and Botanicals in Amaro, Explained”, Louis Catizone, Vinepair.

Citrus polyphenols are FXR agonists (turns it on)​6​.  A gut specific FXR agonist was shown to prevent obesity in a rodent model​7​.

So combining gentian and citrus will activate both bile acid receptors.

A dual bile acid receptor agonist has been shown to prevent Progression of Nephropathy in Diabetes and Obesity.​8​ 

Solubility of polyphenols

Bile acids are made by oxidizing cholesterol.  Cholesterol is a polycyclic hydrocarbon that is fat soluble.  Adding oxygen to this structure makes most bile acids somewhat soluble in water.  The same is true of polyphenols.  They are slightly soluble in water.  This property of being sorta fat soluble, sorta water soluble gives them a detergent property that helps us digest.

An issue with polyphenols is that they are not well absorbed.  If you can get them solubilized, they are more likely to be absorbed.  Another thing that’s sorta fat soluble, sorta water soluble is ethanol.  Polyphenols are more soluble in ethanol than they are in water.​9​

The monks knew what they were doing.

A bile acid.
Gentiopicroside.

Hesperidin, a common citrus flavenone.

Conclusions

Readers of this blog know that I love it when traditional food pathways converge with modern science.  Pliny the elder knew that bitter herbs were good for us. He may have learned that from the Chinese.  If you do a google scholar search for “gentiopicroside tgr5” all of the hits are from 2020 and 2021.  The literature about citrus polyphenols and FXR go back as far as 2016. We are just figuring out WHY polyphenols are good now.

For a long time it has been thought that polyphenols were “good”.  They have been described as antioxidants and hormetic agents.  I like root causes, though.  Perhaps the main mechanism of polyphenols is triggering bile acid receptors, which upregulate AMPK, which upregulates PPARa, which upregulates mitochondrial uncoupling.  Uncoupling proteins are fantastic anti-oxidants.  Perhaps polyphenols are simply “plant bile acids”.

You can of course get citrus polyphenols as supplements.  Citrus polyphenols probably stimulate tgr5 as well as FXR​10​.  But the next time it’s cocktail hour, consider that negroni.  Amaro is also great added to seltzer over ice.   I’ll also leave you with my Camparita recipe.

Camparita

Brad Marshall
A margarita made with Campari
Servings 1

Ingredients
  

  • 1 Oz Tequila Blanco
  • 1 Oz Campari
  • 1 Oz Fresh squeezed lime juice
  • 1 pinch Salt Salt to taste or salt the rim

Instructions
 

  • Pour all ingredients over ice. Salt to taste.

Notes

Image Note: The original uploader was WEEN at Russian Wikipedia., CC BY 3.0 <https://creativecommons.org/licenses/by/3.0>, via Wikimedia Commons

Update: Stappj is a non-alcohol Italian Bitter Seltzer

For those who don’t want alcohol. I can’t vouch for it personally. Also, Raphael added a pathway drawing.

  1. 1.
    Keitel V, Gertzen CGW, Schäfer S, et al. Bile Acids and TGR5 (Gpbar1) Signaling. In: Mammalian Sterols. Springer International Publishing; 2020:81-100. doi:10.1007/978-3-030-39684-8_4
  2. 2.
    He Q, Sha S, Sun L, Zhang J, Dong M. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway. Biochemical and Biophysical Research Communications. Published online August 2016:196-203. doi:10.1016/j.bbrc.2016.05.086
  3. 3.
    Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest. Published online May 15, 2004:1408-1418. doi:10.1172/jci21025
  4. 4.
    Xiao H, Sun X, Liu R, et al. Gentiopicroside activates the bile acid receptor Gpbar1 (TGR5) to repress NF-kappaB pathway and ameliorate diabetic nephropathy. Pharmacological Research. Published online January 2020:104559. doi:10.1016/j.phrs.2019.104559
  5. 5.
    Choi R-Y, Nam S-J, Lee H-I, et al. Gentiopicroside isolated from Gentiana scabra Bge. inhibits adipogenesis in 3T3-L1 cells and reduces body weight in diet-induced obese mice. Bioorganic & Medicinal Chemistry Letters. Published online July 2019:1699-1704. doi:10.1016/j.bmcl.2019.05.038
  6. 6.
    Liu L, Liu Z, Li H, et al. Naturally Occurring TPE-CA Maintains Gut Microbiota and Bile Acids Homeostasis via FXR Signaling Modulation of the Liver–Gut Axis. Front Pharmacol. Published online February 6, 2020. doi:10.3389/fphar.2020.00012
  7. 7.
    Fang S, Suh JM, Reilly SM, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. Published online January 5, 2015:159-165. doi:10.1038/nm.3760
  8. 8.
    Wang XX, Wang D, Luo Y, et al. FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity. JASN. Published online October 31, 2017:118-137. doi:10.1681/asn.2017020222
  9. 9.
    Ariño A, Arberas I, Leiton MJ, de Renobales M, Dominguez JB. The extraction of yellow gentian root (Gentiana lutea L .). Zeitschrift f�r Lebensmitteluntersuchung und -Forschung A. Published online September 26, 1997:295-299. doi:10.1007/s002170050168
  10. 10.
    Yang Y, Tian A, Wu Z, Wei Y, Hu X, Guo J. Finger Citron Extract Ameliorates Glycolipid Metabolism and Inflammation by Regulating GLP-1 Secretion via TGR5 Receptors in Obese Rats. Uzor PF, ed. Evidence-Based Complementary and Alternative Medicine. Published online March 27, 2021:1-11. doi:10.1155/2021/6623379
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30 thoughts on “Campari is a dual bile acid receptor agonist that activates AMPK”

  1. Outstanding. My wife and I developed a fondness for amari and the entire aperitivo tradition on a trip to Italy a few years ago. Looks like this will be an enjoyable tool to keep in the arsenal.

  2. A boulevardier is a better way to consume Campari, IMHO. Even parts whiskey, sweet vermouth, and Campari. It’s a riff on a Manhattan that is just beautiful.

  3. I have a shelf full of Amari and have loved it for quite some time. Interesting to hear about the technical effects of it.

  4. I’m excited to delve into the history and existing research on this. Your blog has been incredible to read Brad I’ve struggle with weight my whole life despite often being touted by friends as “the healthiest eater” they know. I’m wondering, if citrus polyphenols are better absorbed in ethanol, would it make sense to take citrus polyphenol supplements with the campari? or is that overkill?

    1. I recently did an experiment where I heated water and vodka both up to 180 and then saw how much polyphenols they’d dissolve, just based on the cloudiness of the liquid. The vodka absorbed MUCH more. Is that overkill? Hard to say.

  5. Fun article as always! Very interesting about ethanol solubility of polyphenols. My recent regimen of hibiscus and oranges is depending on water solubility but it sounds I have something else to try. Been doing Sherry and Port this past week… after that time to brave some Campari.

    1. Also GLP-1 activating AMPK – as it usually gets triggered by carbs later in the gut which have survived (via encapsulating fiber? thinking of a Break Nutrition podcast where Gabor talked about this) to indicate we are “well fed”, further demonstrating AMPK as a “main throttle” not just a “cellular energy sensor”… Stomping on the gas, as it were.

      PS- Will thyroid hormones play a part in all this at some point? Curious about what exactly they *do*, understanding the T4 vs. T3 and what triggers T4->T3 intracellularly (iirc it happens at the peripheral cells?)

        1. My very amateur level of understanding is something like this:

          Thyroid gland produces T4, and a little T3. T4 and T3 act on the peripheral cells via nuclear transcription factors to do in order to raise metabolism somehow. Reverse T3 is also available, and that blocks T3(?) or prevents it somehow.

          Most of the thyroid hormone coursing throughout your body is T4, but T3 is the “high octane” potent hormone. Much of peripheral regulation is about converting T4 into T3 (raise metabolic rate), or (T4 into reverse-T3?) to inhibit metabolic rate. There are deiodinase enzymes in our peripheral cells (particularly liver & gut, I’m reading?) to perform this, and they are regulated …. somehow.

          There are regulatory hormones (e.g. TSH, TRH) which I believe are a regulatory circuit between the hypothalamus/pituitary and the thyroid, but my amateur understanding is they’re mostly about the brain telling the thyroid to make enough T4 for the peripheral cells to play out their drama of T4->T3-or-rT3. Like the pancreas telling the liver to produce glucose via glucagon if glucose is too low, it’s just making sure there’s enough “stuff” for the system but the real “action” happens at the periphery. TSH is the only one doctors usually test to “test your thyroid” in typical labs your primary care physician cares about. Basically “Is the thyroid producing enough, if TSH is high then something is off, the brain’s saying MAKE MORE HORMONE but the thyroid clearly isn’t responding”

          I have a suspicion this plays into our world in 2 ways:

          1. What the heck is T4/T3/rT3 doing to our peripheral cells, how is it interacting with PPAR, AhR, AMPK, etc?
          2. Is control over the T4->T3/rT3 happening via nerves in the brain (and peripheral nervous system/sympathetic vs. parasympathetic nervous signalling)? Could this be a “counter-regulatory” system where the brain senses what we’re doing with all this sterculia, ampk agonists, high sat fat, uncoupling and “putting the brakes on” so we don’t lose weight… I suspect some of this is happening and we’re going to have to confront this issue somewhere down the line.

          1. On that last point, ““putting the brakes on” so we don’t lose weight…” there’s also a tantalizing question of-

            Which of these interventions we’re toying with, tgr5, ampk, etc. might circumvent the thyroid regulatory system and allow us to burn more calories by virtue of our diet? Are some of them waking up the brain somehow to instigate higher metabolic rate regardless of “set points” and the brain’s desire to keep fat around for a famine?

          2. I haven’t researched it enough yet, but the thyroid hormone receptor is part of the nuclear receptor superfamily that makes a heterodimer with RXR. Sound familiar?

          3. Reverse t3 takes it out of the pool of active t3. This what happens in the ICU so pathogens wont get at it.

      1. Recently, bile acids have emerged as key signaling molecules in the regulation of energy balance in addition to their known role in lipid absorption and cholesterol metabolism (Staels and Fonseca, 2009). They act as ligands for G-protein-coupled receptor (GPCR) and farnesoid X receptor α (FXR-α) to activate thyroid hormones and increase energy expenditure among other functions (Watanabe et al., 2006, Watanabe et al., 2011; Worthmann et al., 2017). Although FXR was found to be important for energy-regulating effects of SG (Ryan et al., 2014), an increase in circulating bile acids is observed after both RYGB and SG (Figure S7F) (Penney et al., 2015). Finally, pepti

        https://www.cell.com/cell-reports/fulltext/S2211-1247(20)31259-6?sf239289978=1

  6. Hopefully other bitters are equally benefical. I use angostura bitters and Jägermeister now and again so fingers crossed.
    Thank you for your all your work Brad. Linda UK.
    Angostura aromatic bitters-
    was first made in 1824 by Dr. J.G.B. Siegert, Surgeon General for Simón Bolívar, in the town of Angostura, Venezuela. Siegert created it to alleviate digestive problems and battle Venezuelan parasites. The House of Angostura is now in Trinidad and Tobago. Production of Angostura is kind of cloak-and-dagger. It’s speculated that the recipe contains over 40 ingredients, but only five people on the planet know the formula.

    Cranberry bitters –
    A Rochester New York family business since 1864, the Fee Brothers make Cranberry bitters which we buy in Marks and Spencer in the UK.

    Campari – 1860 in Italy, and which you have recommended in your blog.

    Amaro Montenegro –
    is a traditional amaro distilled in Bologna, Italy. It is made from a secret blend of 40 botanicals, including vanilla, orange peels and eucalyptus. First produced in 1885.

    Jägermeister –
    Developed in 1934 by Wilhelm and Curt Mast in Germany to a secret blend of 56 herbs, roots and fruits. I like to make the sauce and my son likes to drink shots. Maybe I should have shots too!
    Jägermeister Sauce –
    1 cup cream fraiche
    2/3 cup Jägermeister
    Ginger or mustard to taste.

    There are other, distinctive smaller-batch bitters, such as the extraordinary range made by The Bitter Truth in Germany.

    1. This tweet links to an article about bitters preventing weight gain in rats. Interestingly, these were normal albino rats on normal rat chow, as opposed to the standard experiment where they put mice with a mitochondrial defect on a high-fat, high-PUFA diet.

  7. I just bought some Campari today. I like it, but to me doesn’t taste anything like bile. It tastes more like grapefruit juice with bermagot oil. Pretty good

    1. I got completely entralled with this post and today found myself at one of the better liqour stores in my area. I asked for recommendations for amaro with the lowest alchohol. I walked out with a bottle of Cynar and an Italian vermouth called Antica Formula. They are soooo good and each different. It’s amazing how basically a tablespoon or so sipped slowly is satisfying.

      1. There is a wide range in the gentian content of various Amaro, as this study shows. Licorice, rhubarb and other bittering agents added to Amaro also have interesting effects, though, not JUST citrus and gentian.

  8. Dear Brad,
    I think your blog might have cured my orthorexia! Going vegan for a year back in 2012 made me poorly and since then I have followed various protocols from paleo through to keto and carnivore, all of which had me increasingly limiting my food options. PCOS, gestational diabetes and most recently a sugar and processed food addiction meant I had a singular focus on my food (and that of my family) and then a friend of mine pointed me to your blog and it’s absolutely brilliant! Everything is much more complex and nuanced and everything (apart from seed oils etc) is back on the table, much to my own, and my family’s relief 😅
    Thank you so very much!

  9. Longtime Campari fan here. The interesting thing about this, though, is that Campari is also loaded with sugar. A winemaker friend once sent amaros and aperitifs to the lab for analysis and it came back that they had huge amounts of sugar to balance what is also incredible bitterness. I guess the info on this blog suggests that these bile signals are more important to the body’s self regulation than the calories in sugar are deleterious.

    1. Yup, definitely a lot of sugar. 2015 Brad would have said “absolutely not”. 2021 Brad is more open to possibilities.

  10. TGR5 and FXR (and LXR but might be in an opposite way) seem to be linked with water homeostasis interestingly.

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