The largest contributions to GLP-1s making you lose weight is delayed gastric emptying and early satiety. Some also boost metab. The thing about appetite (desire to eat), is that it somewhat always returns if you had a healthy appetite before meds. Like, even people who do away with their stomachs with bariatric surgery and lose Ghrelin producing cells tanking their appetite suffer from a return to normal levels of hunger a few years after.
When you start losing weight, the body starts adapting immediately. Chronic caloric deficit causes the weight loss stabilizers in the hypothalamus and in other parts of the body to start doing things to defend body weight. It starts upregulating ghrelin synthesis over time, Necessitating higher doses of meds..
The hypothalamic–pituitary–gut axis has been and is being extensively studied to better understand the issues with appetite and appetite regulation.
When the code is properly and permanently cracked, we might see better meds for regulating appetite/hunger.
For now the battle is to keep attacking Ghrelin levels and NPY/AgRp Neurons.
GLP-1s directly prevent the firing of NPY/AgRP neurons causing increased satiety and reducing food seeking behaviour (food noise and appetite). This indirectly drops ghrelin levels. Glp-1s also targets neural stimulation and inhibits Ghrelin release.
GIP on the other hand actually increases appetite Which is why Tirz and Reta feel better than sema. However, GIP when combined with GLP-1RAs hits the NPY/AgRp neurons harder boosting satiety e.t.c with less feelings of bloat or nausea like Sema does.
The glucagon in Reta increases energy expenditure and stimulate thermogenesis.
The reason for all the bullshit I just typed is to explain that once the body keeps sensing a calorific deficit, and deems it as getting worse, it starts upregulating ghrelin production, meaning less stimulus is needed to secrete ghrelin and more inhibition is needed to suppress the firing of NPY/AgRP neurons. Meaning you will need to take more meds to produce similar levels of inhibition.
Also the receptors for GLP1s can get temporarily lost from cell surfaces blunting their actions. Considering that these are primarily neuronal actions, there can be a drop downstream signaling so even though the Meds are hitting the receptors, the nerves just aren't firing enough
When GLP receptors are exposed to continuous high doses of Meds, they undergo internalization. They are either recycled or degraded. This are natural actions designed to maintain balance.
What is causing reduction in the activity of the meds is less of receptor overwork or saturation, but rather due to the brain adapting and upregulating counter measured. Weight loss plateaus happen all the time because of the body's predilection to achieve weight stability. It's not receptor loss or receptor overwork.
So at some point, adding higher dose of meds won't work.
When people take break from Glp-1s, my suspicion is that the increase calorie intake causes the body to taper it's upregulation of food seeking behavior /appetite. It's not really 'receptor refresh'
A better way to tackle this is to add another class of meds to your schedule. If you are on reta, you can step up your reta dose, or add Cagrilintide for example.
Excuse the long post.. Had some free time.
