We all know about leptin resistance by now. Leptin speeds up the metabolic rate and lowers appetite. This helps to keep you lean.

However, people with obesity have high levels of leptin already. How is that? Leptin resistance.

One of the mechanisms by which leptin promotes satiety and energy expenditure is via histamine release in the hypothalamus (R). If histamine signaling doesn’t work, leptin will neither.

It’s quite common for people using anti-histamines to gain weight over time, due to feeling tired and more hungry.

Going a bit further, there is a histamine-AMPK connection and if it becomes dysfunctional, you might start to suffer from excessive hunger and low energy.

How do you fix all of this?

Here are a few ” golden” ways.

Antipsychotic use and obesity

Antipsychotics are known to induce obesity. It’s not just because they block the dopamine receptor which then leads to elevated prolactin, although that also plays a role. But via a variety of other mechanisms as well.

Why talk about anti-psychotics? Because there are a lot of overlapping similarities between someone with antipsychotic-induced obesity and regular obesity where appetite is out of control and energy is very low.

Histamine signaling

Olanzapine (one of the most common antipsychotics) has been shown to significantly up-regulated the hypothalamic histamine receptor 1 (H1R) protein expression. More H1 activation leads to greater AMPK activation, which is usually induced by a low energy state. Elevated H1 expression and AMPK activity lead to enhanced food intake.

It’s not that histamine signaling is bad. In the hypothalamus, histamine neurons are widely distributed and suppress food intake via activating the histamine H1 receptors (H1Rs). It’s that olanzapine causes dysfunction of the H1-AMPK pathway (perhaps also by lowering hypothalamic histamine), which reverses its appetite suppressive effects.

Antihistamines, which block H1, might also upregulate H1 expression, leading to the same conundrum.

Betahistine (an H3 antagonist which leads to higher histamine) co-administration with olanzapine prevented the increase in H1 receptor (R). It could be because olanzapine is an H1 antagonist, which upregulates H1, and increasing histamine, which is an H1 agonist, prevents the increase.

Gold nanoclusters co-treatment with olanzapine significantly inhibited the increase in H1R protein expression and AMPK activity. “The above results suggested that AuNCs (gold) co-treatment suppressed olanzapine-induced H1R overexpression and AMPK signaling dysfunction in the hypothalamus, which resulted in decreased weight gain of AuNCs co-treated rats.” (R)

POMC

Proopiomelanocortin (POMC) neurons are found in the arcuate nucleus (Arc) of the hypothalamus. In the hypothalamus, POMC primarily affects energy balance through the production of several peptides including alpha-melanocyte stimulating hormone (α-MSH), which enhances libido, energy and satiety.

Overactivation of AMPK reduces POMC activity, so reducing excess AMPK might restore it back to normal. Additionally, gold nanocluster co-treatment with olanzapine significantly reversed olanzapine-induced decrease in POMC protein expression.

Brown adipose tissue uncoupling

We all know about brown fat uncoupling. Many people recommend cold water exposure for creating more brown fat which will help with fat loss, but unbeknownst to them, thyroid hormone T3 can also upregulate UCP1. Brown fat is very high in uncoupling proteins, which produce heat instead of energy. More uncoupling = more fat loss.

Reduction in thermogenesis in brown adipose tissue (BAT) also plays a key role in olanzapine-induced obesity.

“BAT thermogenesis is controlled by the hypothalamus. The hypothalamus coordinates outflow signals that drive sympathetic activity to the BAT, controlling thermogenesis (hypothalamus-BAT axis)⁴⁹. In the hypothalamus, the POMC neurons have been reported to be closely related to BAT thermogenesis⁵⁰. Increased expression of POMC in the hypothalamus induced BAT thermogenesis in rats⁵¹.“

In this study, gold nanoclusters co-treatment with olanzapine significantly reversed the reduction of UCP-1 (uncoupling protein), PGC-1α (promotes mitochondrial biogenesis), PPAR-α (promotes proper fatty acid oxidation) and PPAR-γ (promotes adipogenesis. Low levels of PPAR-γ can cause adipose tissue inflammation) expression. (R)

TLR4 activation in the brain

TLR4 is an endotoxin receptor. Activation of this receptor leads to boatloads of inflammation. Olanzapine usage leads to greater expression of TLR4, more inflammation, lethargy and hyperphagia (excessive appetite). People with obesity also tend to have gut dysbiosis and elevated endotoxins in their bodies.

Treatment with endoplasmic reticulum (ER) stress inhibitor (since endotoxin increase ER stress), such as 4-phenylbutyrate or TUDCA, can inhibit olanzapine-induced weight gain and ameliorated olanzapine-induced changes in hypothalamic TLR4 signaling (R, R).

Gold:

• Has potent antimicrobial activity and should help to reduce endotoxin-producing bacteria (R).
• Has anti-inflammatory effects, evident by potently lowering inflammatory markers such as tumor necrosis factor-alpha, interleukin-6 and high-sensitive C-reactive protein in diabetic rats (R).
•  Is neuroprotective and significantly reverses dopaminergic (DA) neuron loss in substantia nigra and striatum of sick mice (R).

Endocannabinoid receptor 1

Endocannabinoid receptor 1 (CB1) signaling is involved in pleasure. It helps make us feel good and enjoy the food we eat. When CB1 becomes downregulated, we start seeking out more palatable foods or more dopamine-releasing activities/drugs.

“Our results showed alterations of the cannabinoid markers in the nucleus accumbens and of orexigenic/anorexigenic markers in the hypothalamus of female rats treated with olanzapine. These molecular modifications could explain the excessive food intake and the resulting weight gain. Moreover, we confirmed that a co-treatment with CB1R antagonist/inverse agonist compounds decreased food intake and weight increment and restored all blood parameters, without altering the positive effects of olanzapine on behaviour.” (R)

Using a CB1 antagonist prevented the decline in CB1 expression. CBD is one of the few potent natural CB1 antagonists out there and should help to upregulate CB1.

Summary

Massive appetite and low energy is caused by dysfunctional H1-AMPK signaling, high TLR4 and inflammation and low POMC, UCP-1, and CB1 expression.

Ultimate fat loss stack to re-modulate your brain (reduce appetite and increase energy levels):

• Gold (lowers H1-AMPK and increases POMC and UCP-1)
• Betahistine/kutaja bark (enhances histamine levels). An even better histamine boosting stack would be 2g histidine, 400-800mcg folic acid and 1/2 tsp kutaja bark
• TUDCA (4-phenylbutyrate is hard to find) (to lower ER stress and TLR4 expression)
• CBD (upregulates CB1)

If I had to narrow it down to 2, I’d use kutaja bark (lower H1-AMPK) and CBD (increase CB1). If gut issues were prominently involved, I’d add in TUDCA.