Is hypothalamic microinflammation involved most of the time? What is it about a high blood glucose level that induces satiety (the hypothalamic ROS generated)?
Catecholamines are also involved and also often sufficient, but not always necessary (and they are easily oxidized/produce ROS in the PFC/striatal regions so it’s not wise to entirely rely on them)
I say this as someone who often eats 3-4 lbs of veggies each day, and sometimes notice they don’t induce satiety. I also can eat 2500 calories of nuts in one go and not have that induce satiety (whereas it would in some people) - I strangely don’t gain weight even if I do this…
Triglycerides have been shown to induce peripheral leptin resistance.20 This raised the question of whether triglycerides could also induce central resistance to leptin or to insulin, two proteins noted for their centrally mediated effects on body weight and cognition. To induce central resistance, triglycerides would have to cross the BBB. However, we could find no studies assessing whether triglycerides could cross the BBB and very limited data on whether triglycerides were even present in the CSF.25 As such, we first determined whether triglycerides were detectable in human CSF. We found that triglycerides were present at about 0.65 mg dl−1, a level representing about 0.6% of blood levels.
We then assessed whether triglycerides could cross the BBB by injecting radioactive triolein into the jugular vein of anesthetized CD-1 male mice. Triglycerides rapidly appeared in brain with accumulation over time. To reach the observed level of nearly 100 μl g−1 at 20 min, the influx rate would have to be about 5 μl g−1 min−1, a rate associated with BBB transport for regulatory proteins.3, 28
We next determined whether triglycerides in the brain could induce leptin or insulin resistance at their CNS receptors. We first performed a dose–response curve to determine the amount of leptin needed to activate the leptin receptor at the hypothalamus. We chose 100 ng of leptin as a dose for further study as it partially activated the receptor. We found that triglycerides blocked the ability of leptin or insulin to activate their canonical signaling pathways. Because of the different structures of triglycerides and proteins, it is unlikely that triolein induces receptor resistance by competitively blocking the binding of a protein to its receptor. To begin to assess how a triglyceride might act to inhibit receptor activation, we injected radioactive leptin ICV with or without triolein and assessed leptin binding throughout the brain. Triolein altered leptin binding in whole brain and in five of the eleven brain regions assessed. However, leptin binding was not decreased, but increased, by triglycerides. This is not consistent with a competitive mechanism for inhibiting receptor activation but suggestive of an allosteric or post-receptor mechanism.
The consequences of triglyceride-induced receptor resistance were assessed by measuring two endpoints of leptin action within the CNS: inhibition of feeding and cognition. Administering leptin ICV decreases feeding and so we here assessed the effect of triolein on the anorexia induced by ICV-administered leptin. We found that leptin induced significant anorexia during the 24 h after its ICV administration. Triglycerides effectively inhibited the leptin-induced anorexia. Previous work has shown that injecting triglycerides directly into the brain impairs learning and memory.23 Here we assessed the effect of serum triglycerides on learning and memory by decreasing serum triglycerides with the drug gemfibrozil. This drug lowers serum triglyceride levels without affecting cholesterol levels and is used clinically to treat severe hyperlipidemia. We found that lowering serum triglycerides not only improved cognition, but that cognition was inversely related to serum levels of triglycerides.
From my understanding the following are useful for satiety:
(i) Volume of food (this is where fiber helps)
(ii) Protein and amino acids – I imagine that certain amino acids are more helpful here than others. For e.g. I have the same issue with nuts. Eggs on the other hand fill me up quickly.
(iii) Omega 3 fatty acids and glutamine simulate Cholecystokinin (CCK) and reduce appetite
(iv) some emulsifiers come in the way of satiety signaling by inhibiting CCK
GLP-1 agonists such as semaglutide also promote satiety by an insane amount. I haven’t been able to get my hands on this yet.
Hm hypothalamic microinflammation is wht DECREASES satiety signals?
Low-grade inflammation in the hypothalamus, a key brain area involved in the regulation of energy homeostasis is shown to blunt signals of satiety after long term high fat diet. The fact that this mechanism can be activated after a few days of hyperphagia before apparent obesity is present led to our hypothesis that hypothalamic inflammation is induced with fat and sugar consumption. Here, we used a free-choice high-fat high-sugar (fcHFHS) diet-induced obesity model and tested the effects of differential overnight nutrient intake during the final experimental night on markers of hypothalamic inflammation. Male Wistar rats were fed a control diet or fcHFHS diet for one week, and assigned to three different feeding conditions during the final experimental night: 1) fcHFHS-fed, 2) fed a controlled amount of chow diet, or 3) fasted. RT-qPCR and Western blot were utilized to measure hypothalamic gene and protein expression, of cytokines and intermediates of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Lastly, we investigated the effects of acute fat intake on markers of hypothalamic inflammation in fat-naïve rats. fcHFHS-fed rats consumed more calories, increased adipose tissue, and showed elevated expression of hypothalamic inflammation markers (increased phosphorylation of NF-κB protein, Nfkbia and Il6 gene expression) compared to chow-fed rats. These effects were evident in rats consuming relative high amounts of fat. Removal of the fat and sugar, or fasting, during the final experimental night ameliorated hypothalamic inflammation. Finally, a positive correlation was observed between overnight acute fat consumption and hypothalamic NF-κB phosphorylation in fat-naïve rats. Our data indicate that one week of fcHFHS diet, and especially the fat component, promotes hypothalamic inflammation, and removal of the fat and sugar component reverses these detrimental effects.
In terms of hypothalamic microinflammation, saturated fatty acids (SFAs) were shown to activate TLR4 and its adaptor MyD88 in the hypothalamus, leading to activation of downstream pathways such as IKKβ/NF-κB, which is a driving force for the expression of inflammatory genes (
). Neurons can be directly responsive to SFAs, since administration of palmitate to primary hypothalamic neurons stimulates inflammatory cytokine expression, ROS production, and endoplasmic reticulum (ER) stress (
). In contrast to SFAs, unsaturated fatty acids (UFAs), and particularly omega-3 UFAs, seem less able to activate inflammatory pathways and can even exert anti-inflammatory effects in the hypothalamus (
), and a fish oil-containing diet was demonstrated to reduce hypothalamic inflammation compared to the proinflammatory effect of a soy-containing diet (
sodium oleate (a FFA) vs monoolein vs triolein. More filling (increases CCK) if you have some digestion byproducts of triglycerides (aka the FFAs or sodium oleate) rather than TGs alone.
The importance of fat storage and metabolism and its influences on long term control of energy balance in humans is well recognised. Welch and colleagues,1 in 1985, observed in humans that infusion of a lipid emulsion into the ileum reduced food intake. They suggested that fat in the small intestine acts as a signal for short term control of food intake; an intravenous infusion of a similar lipid emulsion had no effect on eating. Further experiments with lipid infusions into the jejunum or ileum caused a decrease in food consumption, early satiation,23 and a delay in gastric emptying45; the effects were accompanied by an increase in plasma cholecystokinin (CCK) levels.3 These findings led to the hypothesis that fat acts at a preabsorptive site to decrease food intake and that this effect is indirectly mediated by release of CCK.
In parallel with these results, several animal experiments have been carried out.6-8 The effect of intraduodenal fat on food intake was extensively investigated in rats and pigs; more importantly, the effect was also studied in sham fed rats with an open gastric fistula. In this last experiment, the effect of intraduodenal fat on food intake was investigated independent of its effect on gastric emptying. The results of these experiments support the hypothesis of an intestinal signal induced by intraduodenal fat which initiates a reduction in food intake.
The major products of luminal lipid digestion are monoglycerides and fatty acids.910 In humans, there is evidence that only fatty acids with chain lengths greater than C10 are effective in releasing CCK.11-13 Thus there is a link between fat digestion and the ability of fats to initiate a feedback response on food intake and release of CCK.
but that the enhanced response to fat in these animals was mediated by increased secretion of lipolytic enzymes, which in turn could increase the rate of triglycerides to fatty acids in the small intestine. Taken together, these results imply that free fatty acids are crucial for stimulation of CCK release, gall bladder contraction, and pancreatic exocrine secretory responses.
In agreement with these observations, we have seen here that long chain fatty acids are also crucial for inducing effects on food intake. The experiments largely confirm the observations in rats that hydrolysis of fat is necessary for stimulation of fat induced satiation.22 Intraduodenal administration of fat caused a marked reduction in calorie intake and food consumption. THL, a tool which prevented lipolysis, abolished the effect of ID fat on food consumption. Hildebrand et al found that perfusion of triglycerides concomitant with THL resulted in marked suppression of CCK secretion.26 As CCK has been shown to induce effects on satiety, we believe that the effects initiated by ID fat are mediated by this peptide. Definite evidence, based largely on studies with exogenous CCK, support the following: (1) CCK reduces meal size in animals27-32 and humans1933; and (2) type A receptors seem to be critical.193435 From these results we conclude that the process of satiation is dependent on fat digestion with concomitant release of CCK.
To further support our conclusions, a second approach was taken to investigate the role of free fatty acids on satiety in humans. In this part of the study MCF or LCF were perfused into the small intestine. LCF perfusion resulted in a reduction in calorie intake and food consumption concomitant with a significant increase in plasma CCK concentrations. MCF perfusion was ineffective: there was no effect on food intake or plasma CCK release. These observations suggest that in addition to fat hydrolysis, the chain length of free fatty acids is crucial for initiating an effect on satiety.
The availability of LOX, a potent and selective CCK-A receptor antagonist, has made it possible to test the last part of the hypothesis that CCK is mediating the effects of intraduodenal LCF via peripheral CCK-A receptors. As expected, ID LCF significantly reduced food consumption and calorie intake. Concomitant application of LOX completely abolished the satiation effect of LCF and caused a similar calorie intake as in the control experiment. In rats, the inhibitory effect of intraduodenal sodium oleate7 or Intralipid34 on food intake was antagonised by CCK-A receptor antagonists. Similarly, LOX largely prevented the inhibitory effect of intraduodenal Intralipid on food intake in humans.19 Our present data therefore support and extend these findings: LCF initialises the satiation signal to the brain through release of endogenous CCK; CCK then acts on CCK-A receptors which have been identified on the abdominal vagus.36 It is conceivable that direct activation of afferent fibres through LCF could be an alternative pathway. One type of afferent fibres is sensitive to long chain fatty acids37; furthermore, inhibition of food intake induced by intraduodenal sodium oleate is reversed by bilateral, subdiaphragmatic vagotomy38 or pretreatment with capsaicin.35 It is not clear, however, how CCK could be involved in this last scheme.
Recent evidence has suggested that leptin, the product of the obese gene, may be involved in satiety pathways originating from the gastrointestinal tract. Bado and colleagues39 detected leptin gene expression and immunoreactivity in the gastric fundus. Furthermore, food ingestion caused rapid stimulation of gastric leptin secretion, an effect which was reproduced by CCK administration. In mice, leptin enhances the satiety inducing effect of CCK40suggesting that CCK induced leptin secretion may amplify the intestinal regulation of food intake. In the present study, however, we did not observe any changes in circulating leptin concentrations.
The satiety index of potatoes is not predicted by its glycemic index, glycemic load, or protein and water content. The disproportionately high satiety index of potatoes is thought to be due to protease inhibitors. PL2 was thought to be the primary mediator of this action in potatoes but this paper shows that PL2 is less satiety-inducing than equal quantities of other protease inhibitors found in potatoes. Note that PL2 is only 5% of the protein content in potatoes.
