Inhibiting dopamine breakdown reverses obesity WITHOUT caloric restriction

[EnergeticLeo]

I would not bet much on that. Unless someone is really sick for some reason, only then will drugs work (but it's still a hit or miss). I know someone who is sick and "overweight" (mainly water retention) and used RU486 and nothing. Zero symptom resolution. Same with cypro, progesterone and most other supps. In some cases it's really hard to find the root cause without testing.

But more generally, I'm guessing you do agree that calories in, protein intake, lifting aren't the only things affects weight loss / weight gain? i.e. that there are many other factors that affect energy balance through an impact on hormones

 

[Hans]

I'm guessing you do agree that calories in, protein intake, lifting aren't the only things affects weight loss / weight gain?

Yes but that's more in rare cases and not the norm. People always want to use that as an excuse not to eat right or get off their butts.

 

[Mauritio]

Yet another study showing that the dogma we have been fed for decades - eat less and move more - is little more than a fraudulent lie. Recent studies have already demonstrated that chronic caloric restriction changes body composition for the worse - i.e. despite the weight loss, most of that weight loss is lean muscle mass and is also accompanied by a dramatic drop in the resting metabolic rate (RMR). The contest aptly named "The Biggest Loser" is perhaps the best example of what happens when somebody chronically fasts and exercises at the same time. Those poor people not only regained all the weight they lost during the contest, but felt completely miserable afterwards and found themselves gaining even more weight on a caloric intake that was up to 50% lower than what they were eating before the contest. That, of course, is the guaranteed outcome when their RMR had dropped by about 50%, as a result of participation in the contest. Other human studies with less restrictive regimens demonstrated similarly (proportionally to the restrictiveness of the regimen) alarming results in regards to lean muscle loss, insomnia, cognitive dysfunction, mood changes, etc that can all be traced back to the elevated baseline cortisol that the dogma "eat less, more more" invariably leads to. So, if fasting and torturing ourselves is not the path to slimness and health then what is? Well, if we accept that obesity is an endocrine/metabolic disorder then measures to increase RMR and change the endocrine profile away from stress would be beneficial. One of the main mediators of stress is serotonin. In fact, it is serotonin that is perhaps the major controller of cortisol release (through the 5-HT2C receptor). There are multiple ongoing human studies with drugs that inhibit the synthesis of serotonin - tryptophan hydroxylase (TPH) inhibitors - or drugs that block serotonin at the receptor level, and those have shown great promise so far not only for obesity, but for diabetes, heart disease and even neurological disorders. In other words, serotonin is obesogenic and it induces those effects by lowering of the RMR. Here is just a small list of such studies, for the people who still believe serotonin is the "happy hormone".

Inhibiting serotonin reverses obesity - Nature Reviews Drug Discovery
Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease
Regulation of systemic energy homeostasis by serotonin in adipose tissues - PubMed
Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis - PubMed
Peripheral Selective Oxadiazolylphenyl Alanine Derivatives as Tryptophan Hydroxylase 1 Inhibitors for Obesity and Fatty Liver Disease - PubMed
Serotonin Regulates De Novo Lipogenesis in Adipose Tissues through Serotonin Receptor 2A
Inhibition of Serotonin Synthesis Induces Negative Hepatic Lipid Balance
JCI - Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance
Pharmacologic inhibition of serotonin htr2b ameliorates hyperglycemia and the altered expression of hepatic FGF21, Sdf2l1, and htr2a in db/db mice and KKAy mice
Single or combined ablation of peripheral serotonin and p21 limit adipose tissue expansion and metabolic alterations in early adulthood in mice fed a normocaloric diet
https://onlinelibrary.wiley.com/doi/full/10.1111/jdi.12406

Coincidentally (or not) the recent large study refuting the "serotonin hypothesis" in depression stated the exact same thing as the findings of the Biggest Loser contest - i.e. serotonin has nothing to do with happiness, its main role is as a (negative) metabolic regulator and if it has a role in depression it must be a negative role (i.e. it causes, not relieves depression) due to lowering energy levels in the brain. But I digress, so back to weight loss and obesity. Assuming serotonin is obesogenic then what is the mechanism for its endogenous control? There must be some mechanism through which healthy people manage to keep serotonin in check and thus stay lean/healthy without dieting/exercising. Older studies from the 60s and 70s of the past century suggest that the main endogenous antagonist of serotonin is the neurotransmitter dopamine - the one we are told leads to impulsiveness, instability and craziness. You see, that "crazy" dopamine just so happens to be a potent TPH inhibitor as well, while serotonin happens to be an inhibitor of the dopamine-synthesizing enzyme tyrosine hydroxylase.

https://www.sciencedirect.com/science/article/abs/pii/0006295294902437
Dopamine Inactivates Tryptophan Hydroxylase and Forms a Redox-Cycling Quinoprotein: Possible Endogenous Toxin to Serotonin Neurons
Inhibition of tyrosine hydroxylase activity by serotonin in explants of newborn rat locus ceruleus - PubMed
Serotonin 5-HT1A receptors mediate inhibition of tyrosine hydroxylation in rat striatum - PubMed

So, serotonin and dopamine are largely antagonistic to each other and their levels are inversely correlated. The latter fact has already been confirmed in humans, and it is also well-known that obese people have lower baseline dopamine levels. In light of all those relationships one could surmise that elevating dopamine levels may be beneficial for obesity, by lowering serotonin and thus raising the RMR. While raising dopamine by supplying precursors such as L-DOPA has been used for decades to treat Parkinson Disease (PD), such treatments quickly lose effectiveness and thus the pharma industry started looking at alternative solutions such as inhibiting the breakdown of dopamine by blocking the dopamine-degrading enzyme monoamine oxidase type B (MAO-B). One of the oldest drugs in clinical use for PD is exactly such an MAO-B blocker under the name of selegiline/Deprenyl. That drug is already notorious for being able to delay aging and protect from chronic disease, and it is widely used by celebrities and politicians around the world as an anti-aging and life-extension drug. Well, if the findings of the study below are legit that drug will soon become an even bigger blockbuster. Namely, the study found that using a novel, patented (though identical in pharmacology to selegiline) MAO-B inhibitor lead to increase in thermogenesis/uncopling (and thus RMR), which led to loss of weight without any changes in caloric intake or exercise regimen. According to the study, the MAO-B inhibitor achieved those effects by lowering GABA levels in astrocytes (since MAO-B also synthesizes GABA), but I do not agree with that explanation and maintain that it is the lowering of serotonin by increasing dopamine (through MAO-B) that was the main mechanism of anti-obesity action in this study. Regardless of my opinion, the main takeaway (in the study's own words) is that MAO-B inhibition is a viable mechanism for reversing obesity even on highly obesogenic diet.

@ecstatichamster

Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA - PubMed
A new breakthrough in obesity research allows you to lose fat while eating all you want

"...In a diet-induced obese mouse model, the researchers observed significant slowing in the pacemaker firing of the GABRA5 neurons. Researchers continued with the study by attempting to inhibit the activity of these GABRA5 neurons using chemogenetic methods. This in turn caused a reduction in heat production (energy consumption) in the brown fat tissue, leading to fat accumulation and weight gain. On the other hand, when the GABRA5 neurons in the hypothalamus were activated, the mice were able to achieve a successful weight reduction. This suggests that the GABRA5 neurons may act as a switch for weight regulation. In a new surprising and unexpected turn of events, the research team discovered that the astrocytes in the lateral hypothalamus regulate the activity of the GABRA5 neurons. The numbers and sizes of the reactive astrocytes are increased, and they begin to overexpress the MAO-B enzyme (Monoamine Oxidase B). This enzyme plays a crucial role in the metabolism of neurotransmitters in the nervous system and is more predominantly expressed in reactive astrocytes. This ends up in the production of a large amount of tonic GABA (Gamma-Aminobutyric Acid), which inhibits the surrounding GABRA5 neurons. It was also discovered that suppressing the expression of the MAO-B gene in reactive astrocytes can decrease GABA secretion, thereby reversing the undesirable inhibition of the GABRA5 neurons. Using this approach the researchers were able to increase the heat production in the fat tissue of the obese mice, which allowed them to achieve weight loss even while consuming a high-calorie diet. This experimentally proves that the MAO-B enzyme in reactive astrocytes can be an effective target for obesity treatment without compromising appetite. Furthermore, a selective and reversible MAO-B inhibitor, 'KDS2010', which was transferred to a biotech company Neurobiogen in 2019 and is currently undergoing Phase 1 clinical trials, was tested on an obese mouse model. The new drugs yielded remarkable results, demonstrating a substantial reduction in fat accumulation and weight without any impacts on the amount of food intake."

This study says similar things:
"Certain monoamine oxidase (MAO) inhibitors exhibit beneficial effects, such as reducing adiposity and metabolic disorders; however..."

And shows that selegiline can prevent fatty liver disease:
"Administration of selegiline (0.6 mg/kg body weight) by intraperitoneal injection was found to reduce HFD-induced body weight gain and increases in liver and adiposity coefficients, blood lipids and fatty acid levels. Furthermore, selegiline dramatically reduced the total triglyceride (TG) and cholesterol (TC) levels and lipid accumulation in the livers of HFD-fed mice and palmitic acid (PA)-treated AML-12 hepatocytes."

- Selegiline ameliorated dyslipidemia and hepatic steatosis in high-fat diet mice - PubMed

 

[Highserotonin90]

@Mauritio Too bad Sigma is an antagonist

 

[sugarisgreat]

i found that I didn't lose fat until I went on a high starch diet, and now it's easy to regulate. I think it controlled my cortisol and really was wonderful.

This is my experience too. Low fat, pyruvate, and high carbs/starch is a winning combo for me.

 

[ecstatichamster]

This is my experience too. Low fat, pyruvate, and high carbs/starch is a winning combo for me.

Pyruvate? From what?

 

[sugarisgreat]

Pyruvate? From what?

I use Pyrucet from Ideal Labs. I think it helps me burn carbs better. I am guessing due to low calorie dieting most of my adult life, I was stuck burning fat, rather than sugar.

 

[Highserotonin90]

@sugarisgreat Pyruvate is the end product of burning sugars so you should already have it high.

 

[ecstatichamster]

I use Pyrucet from Ideal Labs. I think it helps me burn carbs better. I am guessing due to low calorie dieting most of my adult life, I was stuck burning fat, rather than sugar.

thought so, just wanted clarity, and thank you!

 

[S.Holmes]

@Hans I lost 4kgs last summer only thing that changed in my life was lisuride. (one bottle in one month)

Awesome. Did you use it topically or orally?

 

[EnergeticLeo]

Yes but that's more in rare cases and not the norm. People always want to use that as an excuse not to eat right or get off their butts.

Ok. Recently I was thinking how it would be better to generate a given rate of weight loss, say 1lb/week, at a higher caloric intake than a lower one, since then the cells have more resources to maintain themselves and there is less risk of a rise in cortisol. Would it not be better to add T3 to a maintenance-calorie diet rather than reducing calories, assuming basic exercise is covered (walking, lifting etc..)?

 

[Hans]

Ok. Recently I was thinking how it would be better to generate a given rate of weight loss, say 1lb/week, at a higher caloric intake than a lower one, since then the cells have more resources to maintain themselves and there is less risk of a rise in cortisol. Would it not be better to add T3 to a maintenance-calorie diet rather than reducing calories, assuming basic exercise is covered (walking, lifting etc..)?

I'd say T3 is good on maintenance and deficit if done right. If the goal is weight loss, you're going have to create a deficit somehow. If you lose weight on 3000cal, then you're still in a deficit. You just need to find that spot for you.

 

[EnergeticLeo]

I'd say T3 is good on maintenance and deficit if done right. If the goal is weight loss, you're going have to create a deficit somehow. If you lose weight on 3000cal, then you're still in a deficit. You just need to find that spot for you.

Cool, makes sense

 

[Mauritio]

@haidut @Hans

In the study they actually looked at Selegiline and it only lead to low, transient weight loss.
So there is something else at play here. Maybe the study authors are right about the mechanism...

" We observed a significantly potent decrease in body weight in KDS2010-treated HFD mice to the level of chow mice within 8 weeks (Figure 6E) without changing their food intake (Figure 6F). In contrast, an irreversible MAOB inhibitor Selegiline showed only a transient reduction in the body weight (Figures S5A-S5D)"

It might also have to do with reversability of the MAO-Inhibition.

"By comparing the irreversible inhibitor selegiline and reversible inhibitor KDS2010, we discovered that KDS2010 showed long-lasting effects compared to selegiline, implying that reversibility of MAOB inhibitor is critical for long-lasting efficacy. "

Interestingly it might have to with brain serotonin!
Selegiline simply might not be as BBB-permeable as the other drugs used. So if we want to make use of this fact then sublingual selegiline would be a better approach, since it likely leads to a higher brain concentration of selegiline than oral use.

"Furthermore, by comparing the BBB-permeable KDS2010 and the less BBB-permeable KDS1524, we discovered that KDS2010 showed a far superior effect than KDS1524, implying that the central MAOB in the brain is a far more effective target for developing anti-obesity drug than the peripheral MAOB. The effect of inhibiting MAOB in the brain can also affect other hypothalamic regions, such as ARC and PVH, where reactive astrocytes are readily observed after HFD (Buckman et al., 2013). "

The transient weight loss by selegiline might have to do with it causing a compensatory increase in the DAO enzyme, so I guess the authors imply that DAO also deactivates dopamine.

"... irreversible inhibitors like selegiline covalently modify the MAOB enzyme and destroy the enzyme itself to turn-on the compensatory mechanism of DAO, whereas reversible inhibitors occupy the active site of MAOB competitively, resulting in an intact MAOB enzyme with no compensatory mechanism (Park et al., 397 2019)."

EDIT:
I just came across this study which shows that selegilie DOES in fact lower body weight quite significantly. Not only that : the mice ate more, weighed less and had higher levels UCP1. Not sure why the difference here, but maybe because of the high dose, which was in IP-injection once daily of about 200mg (HED).
- Selegiline Modulates Lipid Metabolism by Activating AMPK Pathways of Epididymal White Adipose Tissues in HFD-Fed Obese Mice

 

[docall18]

FWIW: I lost 30lbs when I took 1200mg of caffeine a day for two weeks. Maybe it raised my dopamine, (I keep serotonin low with cyproheptadine). I lost the weight over the next month or so, (after the two weeks on caffeine).

My assumption was that my liver dropped fat because of the caffeine and I stored glycogen better and that helped me lose weight, (keeping cortisol at bay longer with better glycogen stores). After this discussion I’m not so sure. I did not change my diet, (I found I needed to eat more so as not to lose more weight). I do eat starch but keep starch and sugar separate typically, (not obsessively).

Hi, have fatty liver and am going to try high dose caffeine. Did you use cypro daily with the caffeine? Did you add anything else, such as vit K? thanks.

 

[EvanHinkle]

Hi, have fatty liver and am going to try high dose caffeine. Did you use cypro daily with the caffeine? Did you add anything else, such as vit K? thanks.

I use cypro at night most nights for better sleep, but didn’t use it “because” of the caffeine. I use vitamin K occasionally for oral health, but haven’t ever used it specifically for my liver. All I used was the caffeine, and I’ve maintained the weight loss.

 

[Mathgirl]

I use cypro at night most nights for better sleep, but didn’t use it “because” of the caffeine. I use vitamin K occasionally for oral health, but haven’t ever used it specifically for my liver. All I used was the caffeine, and I’ve maintained the weight loss.

Do you mind sharing how much cypro?

 

[EvanHinkle]

Do you mind sharing how much cypro?

Like .5-1mg. Very little

 

[docall18]

I use cypro at night most nights for better sleep, but didn’t use it “because” of the caffeine. I use vitamin K occasionally for oral health, but haven’t ever used it specifically for my liver. All I used was the caffeine, and I’ve maintained the weight loss.

Tried the caffeine & k2 for near two weeks. Lost 3kg pretty fast. However not feeling the best. Am pretty sure my cortisol went sky high and made me lose weight, like going on keto diet.

 

[HumanLife]

Like .5-1mg. Very little

Applied on the wrist / stomach or consumed?