Quick hodge podge of ideas I had while on kratom + brain noise'd from some MEATZ (PS, i have successfully identified "brain noise" as some kind of "meat factory farm toxin" vs a general liability of meat. I suspect ketosis modifies how vulnerable I am to it, but my experiment of eating only trader joes meat for a week was a huge success. Although, that's another topic.)
So, the insight came to me that T1DM is now known to be a leptin deficient pathology not purely an insulin deficient one. Peter's work at hyperlipid has unmasked the lie .myth that CNS insulin is metabolic regulating; this is quite consistent with research that demonstrated T1DM animals can be normalized with leptin alone. All this time we were focused on insulin, we didn't stop to consider perhaps insulin was a synthesis catalyst for leptin which is the TRUE metabolic regulation/normalizing substance. The metabolic defects and hyperphagia of T1DM are likely all attributed to the leptin deficiency of chronic hypoinsulinemia/lipolysis. Only chronic unrestrained lipolysis can be attributed to insulin (deficiency), it seems.
It is the leptin that has hepatic LRs and constrains glucose production.
It is the leptin that depolarizes POMC neurons and normalizes MC4rs/MSH.
It is therefore leptin (deficiency) producing diabetic hyperphagia, not insulin deficiency. It merely so happens the latter always causes the former. It is also true most of the hyperglycemia is a leptin deficiency, as the liver has no leptin signalling to inhibit GNG/abnormal fuel use.
The thought twisted in my mind as a parallel to this lesson, I have been so preoccupied with post obesity and the hypotrophic adipocyte as a leptin deficient pathology, perhaps it is appropriate at least clinically and pharmacologically to consider it a hyperadiponectinemia pathology.
We know for example when the mature adipocyte undergoes the diet and exercise treatment, i.e. calories out calories in, i.e. low carb insulin suppression and chronic lipolysis w/o sufficient restoration of lipid via binging on lindt truffles, two things happen to that adipocyte over time.
Leptin declines a lot.
Adiponectin rises also a lot.
The results of successful wt maintenance induce this chronic endocrine signature which is redundant with starvation and dying of malnutrition.
It doesnt really much matter how you induce adiopcyte hypotrophy although i highly recommend the ketogenic diet if you want to stay sane/make things work least against you; NO matter WHAT you do you run into kinks induced by those two asshole adipokines.
Because obesity researchers are morons, as previously described the general consensus is "the more adiponectin, the better!". The mainstream perspective is that adiponectin fights insulin resistance, fights metabolic disorder, makes glucose use better, this hormone rising abnormally excessively after wt loss is a very good thing!
In reality adiponectin is a chameleon. Too little is associated with systemic inflammation, diabetes, metabolic syndrome and obesity. This is true. However, too much however is a clear thrifty phenotype syndrome evolutionarily adaptive in starvation, the function of which is to terminate inflammation in the adipose tissue by shutting down TNF-a. Adiponectin and TNF-a exist on a flucrum and either antagonizes the other. TNF-a is necessary for weight regulation, just as crucial as the balance of MSH/MC4R which is more well known. Adiponectin is to AgRP as MSH is to TNF-a; the former is associated with starvation and its goal is to make you fatter once you finally find a lucky pot of lindt truffles at the end of your week long atkins diet rainbow.
Adiponectin with regard to weight reduction is much more like AgRP than it is this magical mystical diabetes metabolism cure! treatment! Extraordinare! Adiponectin not only antagonizes the lipolytic effect of TNF-a but it is frankly hugely fattening independent of TNF-a...
These data suggest a new role for adiponectin as an autocrine factor in adipose tissues: promoting cell proliferation and differentiation from preadipocytes into adipocytes, augmenting programmed gene expression responsible for adipogenesis, and increasing lipid content and insulin responsiveness of the glucose transport system in adipocytes.
Naturally, obesity/diabetes researchers think this is wonderful. They're stupid.
Here's a decent paper describing the adipocyte endocrine effects of TNFa and talk of inverse relationship/regulation by adiponectin. Please excuse the obesity/diabetes retardearcher perspectives as their job is to develop drugs that lower HgA1c half a point at any cost, in spite of causing cancer and making you an obese whale all the while. By a rule they cannot figure out or understand anything, and if they do incidentally, they must suppress it or lose their job. Just ignore the half cocked interpretation and neturally read the facts of what TNFa does physiologically ( suppressing PPARy, inducing adipocyte IR, inducing very scary ROS that damage ur mitochondriaz etc. ) In fact, if you ignore the emotional lean, it seems pretty clear TNF-a fucking rules for not being a diabetic lardass with zero capacity to use fat tissue for energy.
Here's another paper. This one is even better. Tumor Necrosis Factor-α Induces Apoptosis of Human Adipose Cells:
Furthermore, TNF-α has distinct effects on adipose tissue including induction of insulin resistance, induction of leptin production, stimulation of lipolysis, suppression of lipogenesis, induction of adipocyte dedifferentiation, and impairment of preadipocyte differentiation in vitro.
Um. This is bad? Oh that's right. Diabetes researcher. Tard. Etc.
Reality: TNF-a = inverse shadow of adiponectin. TNF-a is slimming and adiponectin is massively fattening.
What regulates TNF-a? There's a lot written if you investigate, but long story short adiponectin inhibits TNF-a, TNF-a definitely inhibits adiponectin. Adiponectin is synthesized via insulin stimulation within the (post obese/hypoinflammatory / hypotrophic/ PPARy expressing) adipocyte , just like those awesome PPARy expressing TZD drugs. Adiponectin is nature's TZD drug. This promotes the actions of insulin in the adipocyte (read: using glcose/storing energy/being a lardass) and causes new adipocytes to form like a yo-yo dieter binging on little debbie cakes. Read above for more gory details.
So, enough background of why this is important + you should care. On to my great idea, that the post obese state might not require leptin replacement but perhaps would respond well to adiponectin inhibition. Other than TNF-a, what might inhibit adiponectin, antagonize it, regulate it?
I discovered the 5ht2a on the adipocyte, unlikely enough, is a negative regulator of adiponectin; serotonin is inflammatory, 5ht2a agonism of the adipocyte inhibits adiponectin release. Very intriguing, especially considered my favorite leaf is a 5ht2a ANTAGONIST, i.e. adiponectin promoting.
This might explain why I am responding so well to TNF-a augmentation, and it would explain the "antiketogenic/fattening high dose kratom" effect. I originally attributed the vanishing ketone effect of prolonged or high dose kratom to SNS ablation of MORs, but i disproved this idea when I observed vicodin progressively improved my ketosis the more of it I took. Pure opiates did not at all suppress ketones and progressively darkened them the more I took, which is inconsistent with my hypothesis MORs just suppress SNS tone to the point of inhibited ketogenesis.
Something else about kratom is antiketogenic/perhaps neutral of weight. I now realize that "thing" is likely 5ht2a antagonism and overexpression of adiponectin. Kratom is weight inhibiting via MSH and MORs, but it is also antiketogenic and lipolytic by contributing to adiponectin overexpression from 5ht2a antagonism. Kratom, therefore, has weight gain promoting as well as inhibiting effects (although anecdotally, in practice, it's at LEAST weight neutral and often very weight inhibiting as the MOR / MSH effect is hierarchical)
(As an aside, this made a big light bulb "aha" in my brain when I recalled that risperidone is a 5ht2a antagonist. We know many cases of insanity are caused by CNS infections which specifically involve systemic inflammation. Those cases are likely to respond well to risperidone, which hypothetically would increase adiponectin and reduce systemic inflammation. Indeed, my hypothesis was correct and research demonstrates risperodone increases adiponectin above baseline, which is all the more remarkable considering APs are otherwise obesigenic and may contribute to metabolic dysfunction, a profile which is almost always found with abnormally low adiponectin.
Responding to risperidone is therefore perhaps a marker for infection/systemic inflammation underlying CNS dysfunction, as the drug specifically tropic of antinflammatory adiponectin. NAC is also similar, another substance/ drug that inhibits TNF-a and produces antinflammatory effects. Moving on, psychiatric tangent aside!)
So yes it is quite ironic that I have discovered kratom helps so much, but my lynchpin hypothesis that the post obese state is a disorder of obesigenic hyperadiponectinemia would only be worsened by the plant. But then again, this easily explains the very depressed ketones I am apt to develop with several days of kratom use, and the total loss of the MOR-like ketogenic enhancement that demarcates very low dose kratom use. The 5ht2a antagonism has become so great adiponectin is overexpressed and impairing TNF-a expression or at least its lipolytic effects.
It appears , at least for me, a 5ht2a agonist to counterbalance might be therapeutic... or continue to take the TNF-a boosting ibuprofen moderately every day. It's a tremendous help.
The last piece of adiponectin/TNF-a related trivia will touch upon my discovery these adipokines interact with the female reproductive system and progesterone. The placenta secretes both adiponectin and progesterone in quantities; this is instrumental to facilitating adipogenesis and fat storage for pregnancy, of course. However, what is not as readily apparent or obvious is that adiponectin not only facilitates pregnancy fat gain + adipogenesis, but it is perhaps true adiponectin receptors are necessary for normal for progesterone sensitization that is require for successful pregnancy. Here is an interesting study suggesting TNF-a might antagonize or block progesterone receptors, antagonize progesterone ability.
However, it is important to convey these findings immediately because they may shed light on many unexplained physiological phenomena pertaining to adiponectin, progesterone and TNFα. For example, while it is well known that TNFα opposes the effects of adiponectin on cells (15), a recent study also showed that TNFα inhibits the effects of progesterone in rat ovary cells (16). Hence, there is already evidence that these findings are more than a mere artifact of the in vitro assay.
This is eye opening and extremely exciting (and terrifying). I have always intuited the post obese female is hypersensitive to the fattening effects of progesterone, and here is outlined a putative mechanism; hyperadiponectinemia, ablated TNF-a, induces a lack of regulation of progesterone mediated adipogenesis/fattening. IF TNF-a is a general progesterone antagonist, this validates the popularity of motrin for menstrual complaints (most of which are partially psychiatric, even if no female wants to admit progesterone is depressive/dysphoriant/miserable).
I also had the flash insight that it may be true ibuprofen is an abortifactant in early pregnancy. Skip the plan B: Just pop a handful of ibuprofen. If the drug is a progesterone antagonist, for women particularly with a low adiponectin tone (e.g. obese/diabetic/IR) then using motrin might make or break the pregnancy...or have teratogenic effects from impaired implantation/blood flow in very early pregnancy.
Indeed, my insight revealed itself true... 2.4 xs higher risk for spontaneous abortion in the first trimester if using NSAIDs.
Women who take even a small dose of painkillers such as ibuprofen early in their pregnancy more than double their risk of suffering a miscarriage, research shows.
The findings prompted medical experts to advise mothers-to-be to avoid taking the drug and instead to use paracetamol for pain relief. Taking any painkillers from the class of medicines known as non-steroidal anti-inflammatory drugs (NSAIDs) – such as ibuprofen, naproxen and Diclofenac – in the first 20 weeks after conception increases the risk of miscarriage by 2.4 times, the study found.
Wow.
To recap:
TNF-a rules, adiponectin sucks. BIG TIME.
TNF-a is regulated by adiponectin and vice versa.
5ht2a agonists inhibit adiponectin; sadly, mitragynine is therefore partially fattening/inhibits ketogenesis (unlike a pure MOR/MSH agonist). This can be countered with TNF-a agonists or perhaps 5ht2a agonists.
Risperidone induces adiponectin expression to DESTROY inflammation of the body, as expected and this drug is likely particularly effacious in mental disorders involving significant inflammation e.g. ur ESR/CRP is nuts from bugs in your brain.
An unlikely surprise, progesterone/adiponectin have a reciprocal relationship perhaps, both are placental hormones, TNF-a a natural antagonist of adiponectin may have antiprogesterogenic activity. This explains the oft reported complaint of weight reduced/obesity prone females such as woo absolutely DYING if our shitty bodies make this crap. Literally q2h hypoglycemia, omfg!
Ibuprofen is an abortifactant and teratogen?
Ibuprofen is a key weight loss drug?
All in a day woo's work....doing more than people paid to think/discover/unmask truth while I rant on twitter via some insulin mediated/kratom addled brain buzzing.