Nicotine may help with weight control due to effects on the GLP-1 receptor

Sunday Confessional; and causes of leg edema or sodium retention, leading to leg edema. Salicylate/NSAID excess is one cause. Lack of protein adequacy in the diet is another, or Liver disease.

Mentioning GLP-1 and trendy Ozempic/semiglutide yesterday made me curious about how nicotine helps control weight. It is known (to dietitians) that women may smoke because it helps them stay thinner, but why does smoking tobacco do that?

• A) Nicotine causes nausea if too much is used, and that is kind of an obvious symptom, when too much is used. But that isn’t enough of an explanation for why nicotine also helps with weight control when not used in excess…

• B) Research has shown that nicotine use does effect GLP-1 metabolism by acting as an agonist of the GLP-1 receptors which would directly be affecting appetite signaling in the same way as if GLP-1 levels had been increased . . . and that would reduce appetite which can lead to easier weight loss. Nicotine acts as an agonist to the GLP-1 receptor - that means it is a little like taking GLP-1 itself.

Dietitian confession - about a month ago, I was so frustrated with being tired, and with my excessive appetite and increased weight, that I started coffee and nicotine lozenges again. The coffee was for energy/alertness (it helps my ADHD) and the nicotine, confession, was because it did help me lose weight with no effort when I had first started it in 2021. I went from a size 10 to a size 8 that summer without even noticing really. This year, or since last summer, I have been struggling with “salicylate sensitivity” and edematous, puffy weight gain that could change 5-10 pounds between morning and evening.

Cholinergic dysfunction may be causal for the water retention. I had stopped the nicotine lozenges during the apparent ‘salicylate sensitivity’ because mint flavor is a salicylate source, so I had expected trouble when I tried it again. BUT, I have been less likely to get puffy during the day now and I have been eating a lot more salt too. I haven’t added back the obvious salicylate sources though, and testing a little bit of it seems to still show a problem. Food sensitivity is very confusing.

The good news, or the confessional news, the nicotine lozenges have reduced my appetite. I have lost some of the weight I had regained and I have also been less likely to get puffy legs during the day - even while scarfing mint lozenges ;-) all day, which should be a salicylate source.

So, why? What is going on in my body? Were chimeric spike effects causing cholinergic dysfunction that was causal of puffy edema? and adding the nicotine and coffee back helped restore cholinergic function? and increase GLP-1 receptor function?

Spoilers/tl;dr -

• Nicotine does help directly with weight loss and reduced appetite by acting as an agonist to the GLP-1 receptor. It isn’t promoting GLP-1 - it is directly acting as if it were GLP-1. Oh, wow, News to Know.

What’s going on with my body?

• I am genetically likely to not breakdown salicylates well, or other benzene ring molecules, and I was drinking a lot of Wormwood tea which is a strong salicylate in the essential oil form - I couldn’t find other info on the tea.

• Why the mint lozenge salicylate isn’t affecting me now, I don’t know. Or the nicotine is helping cholinergic function and GLP-1r function more than the mint matters. I don’t know.

• I have been eating plenty of salt lately as too low of sodium intake is yet another cause of leg edema/leg swelling. During my sodium sensitive months, I had eventually stopped using salt altogether, but then that was too low once I cut out the excess salicylates.

• Too much carbohydrate intake is also a potential short-term cause of sodium retention and swelling, and I do occasionally eat way too much of something. Binge overeating is a genetic risk for me, and a behavior problem I have had to work on.

What is GLP-1? and What does it do for us?

GLP-1 is a hormone produced by the gut and it is involved in the complex regulation of hunger and satiety. Many appetite hormones work together and some increase appetite like ghrelin, and others reduce it, like GLP-1. Other roles of GLP-1 are to slow the emptying of the stomach contents, stimulate release of insulin, and it helps reduce inflammation. (supergut.com)

Nicotine is also an agonist of GLP-1 receptors in the brain - it acts as if you had produced more GLP-1 for yourself.

. . . Oh, that is how nicotine helps with appetite control and promotes weight loss. It acts just like GLP-1.

. . . Skip the Ozempic, consider trying a nicotine lozenge or gum instead.

The physiology involved with nicotine use suggests that it is an agonist of GLP-1 brain cells and acts similarly to GLP-1. Satiety - feeling satisfied and done eating, occurs after stimulation of the GLP-1 receptors. That nicotine stimulates those receptors seems to be a natural mechanism for also producing ‘satiety’, satisfaction at intake of sufficient amounts of nicotine. Mice made to not have functioning GLP-1 receptors will consume more nicotine than wild-type mice. (Tuesta, et al., 2017)

Abstract: “Tobacco smokers titrate their nicotine intake to avoid its noxious effects, sensitivity to which may influence vulnerability to tobacco dependence, yet mechanisms of nicotine avoidance are poorly understood. Here, we show that nicotine activates glucagon-like peptide-1 (GLP-1) neurons in the nucleus tractus solitarius (NTS). The antidiabetic drugs sitagliptin and exenatide, which inhibit GLP-1 breakdown and stimulate GLP-1 receptors (GLP-1Rs), respectively, decrease nicotine intake in mice. Chemogenetic activation of GLP-1 neurons in NTS similarly decreases nicotine intake. Conversely, Glp1r knockout mice consume greater quantities of nicotine than wild-type mice. Using optogenetic stimulation, we show that GLP-1 excites medial habenular (MHb) projections to interpeduncular nucleus (IPN). Activation of GLP-1Rs in the MHb-IPN circuit abolishes nicotine reward and decreases nicotine intake, whereas their knockdown or pharmacological blockade increases intake. GLP-1 neurons may therefore serve as “satiety sensors” for nicotine that stimulate habenular systems to promote nicotine avoidance before its aversive effects are encountered.” (Tuesta, et al., 2017)

Ozempic and Wegovy (brand names), are semaglutide (generic drug name) medications used for weight loss,

. . . and they also have been studied for use to support smoking cessation or to improve blood glucose levels in Type 2 Diabetes.

The medications Ozempic (R) (semaglutide) or Wegovy (R) mimics the effects of GLP-1 but produces a synthetic version of it, rather than increasing natural levels.³ GLP-1 is a hormone that promotes the liver secreting more insulin and less glucagon.^{1, 2}.

1. Ozempic: 7 things you should know, (drugs.com).

2. Ozempic for Type 2 Diabetes: 4 Ways Ozempic Works to Improve Blood Glucose Levels, (goodrx.com).

3. »> Natural GLP-1: How to Produce Satiety Hormones Without Drugs, (supergut.com).

Ozempic has been shown to be quite dangerous and regain of weight is likely once the medication is stopped. A video by Peter Attia, M.D., Cause for caution with weight loss drugs like Ozempic, (Youtube):

The use of medications that are also agonists to the GLP-1 receptor have been studied for use to help with smoking cessation. (Lengsfeld, et al., 2023) Use of a GLP-1 receptor agonist seems to help more with reducing weight gain during smoking cessation than directly reducing the craving for tobacco, but it may help reduce cravings by reducing the increase in dopamine in response to use of nicotine. (Herman and Schmidt, 2024)

“Preclinical studies suggested that nicotine activates GLP-1 neurons [27] while GLP-1 analogues may lead to modified nicotine-induced effects on the mesolimbic dopamine system [28], abolishing nicotine reward and decreasing nicotine intake [27]. In humans, a preliminary study investigating exenatide for smoking cessation in individuals with prediabetes or overweight found increased smoking abstinence rates (46.3% versus 26.8%) and a tendency of lower craving and post-cessation weight compared to placebo after 6 weeks [29].” (Lengsfeld, et al., 2023)

What has been discovered regarding GLP-1 receptor agonists and nicotine cessation?

• “GLP-1R agonists decrease nicotine withdrawal-induced hyperphagia and body weight gain. [Hyperphagia: “an extreme desire to eat food without satisfaction”.]

• In animal models, GLP-1R agonists decrease voluntary nicotine taking and seeking.

• The effects of GLP-1R agonists on smoking behavior in clinical studies are less clear.

• GLP-1R agonists may ameliorate nicotine withdrawal-induced cognitive deficits and mood disorders.” (Herman and Schmidt, 2024)

Google AI summary

Okay, question one is answered - nicotine helps with weight loss in almost exactly the same way as GLP-1, because it is also an agonist for GLP-1 receptors.

. . . That leads me to question 2 - is leg edema related to GLP-1 in anyway?

The answer is maybe. Generalized edema was a side effect of a GLP-1 agonist medication, Albiglutide, in a case study report. Stopping use of the medication caused the generalized edema to stop. Albiglutide is a modified form of GLP-1 which our natural enzyme can’t break down properly, so it only needs to be injected once a week. (Aziz, et al., 2018) If your body can’t break down something, then an excess may accumulate more easily than in normal function.

What is albiglutide?

“Albiglutide is a once-weekly glucagon‐like peptide‐1 (GLP-1) agonist. Albiglutide develops through the fusion of two repeats of human GLP-1 molecules to recombinant human albumin. The GLP-1 dimer was used to avoid potential reductions of the interaction of the GLP-1 moiety of the monomer with its receptor in the presence of albumin. A single amino acid replacement (alanine→glycine) renders the molecule resistant to dipeptidyl peptidase-4 inhibitor (DPP-4).” (Aziz, et al., 2018)

The physiologic plot thickens - albumin was used to form albiglutide. Is it involved in natural GLP-1 too?

The answer is No, it looks like the fusion of human albumin with GLP-1 was research into making a medication that lasts longer/has more obvious effects. (Kim, et al., 2013)

The problem with making a natural protein into something that lasts an abnormally long time, is that more obvious negative side effects are also likely.

So, is a modified albumin that couldn’t be broken down normally what disrupted fluid balance for the patient taking albiglutide?

Maybe yes, albumin not only acts on fluid balance within the blood, but also through signaling mechanisms. (Brave AI summary)

Does nicotine or nAChRs have anything to do with albumin? No, varied searches suggest no direct effects. (Summary)

• Liver disease is associated with reduced albumin levels. (Summary)

• Inadequate protein intake - protein malnutrition causes edema due to less production of the blood proteins, albumin and globulin. (lsuagcenter.com, Protein (Lesson 4))

• Excessive carbohydrate intake or a sudden increase can cause edema from increased sodium retention. (Nutritional Deficiencies, viewable at ScienceDirect/Sodium Retention)

• Autoimmune antibodies against albumin are known and that would negatively impact albumin which would add to edema risk.

• NSAID or salicylate excess causes sodium retention, leading to edema. (Anti-inflammatory Drugs and the Kidney, viewable at ScienceDirect/Sodium Retention)

Salicylate/NSAID sensitivity, Wormwood, and essential oils

Salicylate sensitivity or something in foods does seem to directly trigger the leg swelling for me. When I was drinking Wormwood tea daily earlier in the summer, pre hair loss, that seemed to directly lead to worse leg swelling. I wasn’t using nicotine lozenges during that time period.

Salicylate and NSAID intake in excess are direct causes of sodium retention and genetically I simply may need to avoid excessive use of salicylate type chemicals (anything with benzene rings, chemical model of the salicylate molecule and its benzene ring) - simple answer. I was drinking too much Wormwood tea - which I suspected but it may have some addictive qualities. It is kind of a stimulant. I had to work a bit to stop use of it even after I suspected it was causing problems. Brave AI says thujone is not classically addictive but may cause a dependence effect and have some withdrawal symptoms, summary. I have the thujone containing Wormwood tea, rather than Sweet Wormwood.

“Sodium retention is the most common renal side effect associated with NSAID therapy. The syndrome is clearly related to inhibition of the potent natriuretic and diuretic effects induced by prostaglandins, especially in those conditions in which high renin activity is present.^20” Anti-inflammatory Drugs and the Kidney, Andrew A. House, Claudio Ronco, in Critical Care Nephrology (Second Edition), 2009 viewable at (ScienceDirect/Sodium Retention)

In addition to wintergreen essential oil, wormwood essential oil does have a risk for salicylate excess and oils of birch, parsley seed, pennyroyal, calamus and sassafras are also mentioned. (The urinary system, Robert Tisserand, Rodney Young PhD, in Essential Oil Safety (Second Edition), 2014, viewable at ScienceDirect/Salicylic acid, methyl ester).

I noticed after having run out and then replaced, that Carrot seed essential oil (one drop in a beverage) gave me leg swelling symptoms and I have tried pennyroyal oil topically - good to know it is mint family herb with toxicity risks if used in excess. Celery seed oil might also be a salicylate source as it is also in the parsley plant family and so is fennel. I had noticed Fennel essential oil as an edible oil or too generous use topically, seemed to be a problem, and I stopped using Clove essential oil as an edible oil because it definitely caused the salicylate symptoms - it is pain relieving topically on tooth ache.

“Parsley (Petroselinum crispum) and carrot (Daucus carota) are both members of the Apiaceae family, commonly known as the Parsley or Carrot family.” (Brave AI summary)

Photo by Jordan Christian on Unsplash

Albumin's Fluid Balance Role, (Brave AI summary)

Albumin, a major protein in blood plasma, plays a crucial role in maintaining fluid balance by signaling functions, (van de Wouw and Joles, 2021), in addition to its traditional osmotic pressure-regulating mechanism. (Hankins, 2006) Here are the key findings:

• Nitric oxide (NO) signaling: Hypoalbuminemia (low albumin levels) directly increases NO production in endothelial cells, leading to reduced NO sensitivity in vascular smooth muscle cells. This suggests that albumin regulates NO signaling, which is essential for vasodilation and blood pressure control, influencing fluid balance (Source: “Albumin is an interface between blood plasma and cell membrane, and not just a sponge” - van de Wouw and Joles, 2021)

• Vascular barrier integrity: Albumin interacts with integrins, regulating vascular barrier integrity and preventing excessive protein leakage into the urine. (van de Wouw and Joles, 2021)

• Endothelial cell signaling: Albumin dose-dependently restores LPC-induced inhibition of vasodilation, indicating its role in modulating endothelial cell signaling pathways. (van de Wouw and Joles, 2021)

• Renal tubular uptake: Albumin is taken up by proximal tubule epithelial cells through receptor-mediated endocytosis, preventing urinary loss and maintaining fluid balance. (van de Wouw and Joles, 2021)

In summary, albumin regulates fluid balance by signaling functions, influencing NO production, vascular barrier integrity, endothelial cell signaling, and renal tubular uptake. These mechanisms complement its traditional osmotic pressure-regulating role, highlighting the complexity and multifaceted nature of albumin’s involvement in maintaining fluid homeostasis.

Follow up

• What specific signaling pathways are activated or inhibited by albumin in endothelial cells and vascular smooth muscle cells?

• How does albumin's regulation of nitric oxide signaling impact blood pressure control and fluid balance in various physiological and pathological conditions?

• Are there any specific receptors or binding proteins involved in albumin's interactions with integrins and endothelial cells, and if so, what are their functions?

1. (Hankins, 2006) Hankins J. The role of albumin in fluid and electrolyte balance. J Infus Nurs. 2006 Sep-Oct;29(5):260-5. doi: 10.1097/00129804-200609000-00004. PMID: 17035887. https://journals.lww.com/journalofinfusionnursing/abstract/2006/09000/the_role_of_albumin_in_fluid_and_electrolyte.4.aspx

2. (van de Wouw and Joles, 2021) van de Wouw J, Joles JA. Albumin is an interface between blood plasma and cell membrane, and not just a sponge. Clin Kidney J. 2021 Oct 5;15(4):624-634. doi: 10.1093/ckj/sfab194. PMID: 35371452; PMCID: PMC8967674. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967674/

3. britannica.com, Serum albumin | Blood, Plasma, Transport | Britannica

4. lsuagcenter.com, Protein (Lesson 4)

Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List

(Aziz, et al., 2018) Aziz K, Shahbaz A, Zarghamravanbakhsh P, Ahmed SI, Sachmechi I. Generalized Edema Caused by Albiglutide: A Case Report. Cureus. 2018 Jun 13;10(6):e2801. doi: 10.7759/cureus.2801. PMID: 30116680; PMCID: PMC6089702.

(Herman and Schmidt, 2024) Herman, R.J., Schmidt, H.D., Targeting GLP-1 receptors to reduce nicotine use disorder: Preclinical and clinical evidence, Physiology & Behavior, Vol 281, 2024, 114565, ISSN 0031-9384, https://doi.org/10.1016/j.physbeh.2024.114565 https://www.sciencedirect.com/science/article/abs/pii/S0031938424001100.

(Kim, et al., 2013) Kim YM, Lee SM, Chung HS. Novel AGLP-1 albumin fusion protein as a long-lasting agent for type 2 diabetes. BMB Rep. 2013 Dec;46(12):606-10. doi: 10.5483/bmbrep.2013.46.12.106. PMID: 24195794; PMCID: PMC4133866. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133866/

(Lengsfeld, et al., 2023) Lengsfeld S, Burkard T, Meienberg A, Jeanloz N, Coynel D, Vogt DR, Hemkens LG, Speich B, Zanchi D, Erlanger TE, Christ-Crain M, Winzeler B. Glucagon-like peptide-1 analogues: a new way to quit smoking? (SKIP)-a structured summary of a study protocol for a randomized controlled study. Trials. 2023 Apr 20;24(1):284. doi: 10.1186/s13063-023-07164-9. PMID: 37081574; PMCID: PMC10120253. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120253/

Salicylic acid, methyl ester, The urinary system, Robert Tisserand, Rodney Young PhD, in Essential Oil Safety (Second Edition), 2014, viewable at (ScienceDirect/Salicylic acid, methyl ester).

Sodium Retention, 1) Nutritional Deficiencies, Judy Fuentebella MD, John A. Kerner MD, in Pediatric Clinics of North America, 2009, and 2) Anti-inflammatory Drugs and the Kidney, Andrew A. House, Claudio Ronco, in Critical Care Nephrology (Second Edition), 2009 — viewable at (ScienceDirect/Sodium Retention)

(Tuesta, et al., 2017) Tuesta LM, Chen Z, Duncan A, Fowler CD, Ishikawa M, Lee BR, Liu XA, Lu Q, Cameron M, Hayes MR, Kamenecka TM, Pletcher M, Kenny PJ. GLP-1 acts on habenular avoidance circuits to control nicotine intake. Nat Neurosci. 2017 May;20(5):708-716. doi: 10.1038/nn.4540. Epub 2017 Apr 3. PMID: 28368384; PMCID: PMC5541856. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541856/ Pdf: https://www.dropbox.com/scl/fi/mpd8eq518m6ulmvukigdz/Kenny-1-nn.4540.pdf?rlkey=tii8xdgriv9ykaqa7aodrl0tt&dl=0

1. drugs.com, Ozempic: 7 things you should know, Medically reviewed by Carmen Pope, BPharm. Last updated on Sep 28, 2023, drugs.com, https://www.drugs.com/tips/ozempic-patient-tips

2. Billingsley, A., Ozempic for Type 2 Diabetes: 4 Ways Ozempic Works to Improve Blood Glucose Levels, Written by Alyssa Billingsley, PharmD, Reviewed by Farah Naz Khan, MD, Published on November 27, 2023, goodRx.com, https://www.goodrx.com/ozempic/how-does-ozempic-work

3. Supergut Team, Natural GLP-1: How to Produce Satiety Hormones Without Drugs, by Supergut Team, Nov 06, 2023, supergut.com, https://www.supergut.com/blog/natural-glp-1-how-to-produce-satiety-hormones-without-ozempic