copy/paste from my FB post directed at paleopeeps (because its sunday and im lazy)
We all know about insulin, leptin and ghrelin – the appetite regulating hormones. Insulin is secreted in response to glucose, leptin is secreted by fatcells so its presence depends on fatmass and ghrelin is secreted in your stomach in response to CCK and also in response to the mechanical fullness/emptiness of the stomach… easy and simple right. Well actually everything that gos on inside the body is controlled by the brain – that goes for EVERYTHING. Appetite is regulated by the hypothalamus. NPY/AgRP neurons in the hypothalamus stimulate appetite by producing two neuropeptides — neuropeptide Y (NPY) and agouti-related protein (AgRP), that inhibit the activating of satiety neurons and stimulate melanin-concentrating hormone (MCH) in the lateral hypothalamus. This enhances appetite and decreases metabolism and energy expenditure. Insulin and leptin inhibit the NPY/AgRP neurons. Ghrelin stimulates them. The action of these hormones inside the brain is totally different than in the rest of the body. Insulin`s role in the brain is to decrease energy intake. That is called negative feedback. When energy stores are full, circulating insulin is high >> high insulin in the central nervous system increases glucose (contrary to the effect that high insulin has in the rest of the body = decreasing glucose and increasing hunger) and thus decreases feeding behaviors. So in the brain, insulin is its own counterregulatory hormone, and therefore insulin`s function in the brain produces features of insulin resistance.
We all know about the causes of obesity: leptin resistance and/or insulin resistance = there is plenty of leptin or insulin circulating in the bloodstream but the receptors in the hypothalamus are “death”. Leptin is produced in subcutaneous adipose tissue so the more of it you have, the higher leptin levels you have. This would provide a negative feedback loop releasing fatty acids from adipose cells. Leptin resistance not only happens when receptors have gone death but also when only a low level of this leptin is reaching the hypothalamus. Insulin and leptin use many of the same neurons, receptors and the same messengers to control metabolism so I guess that hypothalamic insulin resistance could be the cause of leptin resistance, but it is not the sole cause because many of overweight individuals remain insulin-sensitive, and not all insulin-resistant persons are overweight. Enter the blood-brain barrier. The blood-brain barrier is semipermeable along the arcuate nucleus to allow the passage of certain proteins but prevent the entrance of others. Leptin and insulin can cross the barrier. Problems in the transport of leptin have a role to play in peripheral leptin resistance. We know that leptin injections straight to the brain work, but it doesn’t work peripherally. Leptin transport is also inhibited in starvation and by hypertriglyceridemia. There have been mice studies that show that triglycerides induce leptin resistance- no human studies ofcourse…. Elevated triglycerides also stimulate ghrelin transport – explains ghrelin entrainment patterns. Ok, so what causes triglyceride levels to increase? Au contraire to Dr. Peat, fructose seems to have something to do with it. BUT only if consumed in excess – what that excess is is personal as well as not very well studied. We know that also sucrose in excess can elevate triglycerides causing leptin resistance and subcutaneous obesity.. So leptin resistance is connected to subcutaneous adiposity – that doesn’t really have much to do with diabetes 2 right? How about insulin? We all know that insulin is produced by the pancreas and it’s main function is to regulate the availability and storage of glucose and fatty acids. Insulin resistance happens when insulin receptors in tissues become less responsive to insulin resulting in hyperinsulinemia >>> type 2 diabetes.
Here comes the part where Peat seems to be on to things: triglycerides do not impair insulin transport over the blood-brain barrier - certain free fatty acids do. Trans fats and omega-6 unsaturated fatty acids are responsible for an inflammatory response in the insulinreceptors. BUT certain sugars like fructose also appear to be pro-inflammatory for the insulin receptors.. what is news is that these inflammatory processes occur not just in the liver and muscles, but also within the hypothalamus. The issue that I have with Peat`s theory is that the research I`ve read does not make omega 6 fatty acids the PRIME culprit but point to one single longchain saturated fatty acid.
Thaler et al. , Schwartz et al and Benoit et al. showed that one particular long chain saturated fatty acid — palmitic acid — causes inflammation and reduces insulin sensitivity in the hypothalamus, leading to overeating and obesity.
This is why I propose that fructose be acknowledged as a PARTIAL or “coculprit” to hypothalamic insulinresistance: In lean and healthy individuals, fructose at reasonable levels is converted to glucose in the liver, and brief excess is then stored as glycogen in the liver and muscles. But in excess, fructose is converted to fat of two types — triglycerides and one particular fatty acid. Can you guess which fatty acid? Yep, palmitic acid, the fatty acid associated with brain insulin resistance. The excess fat is accumulated in the liver (fatty liver disease) which results in hepatic insulin resistance.
So here gos, hate me if you will: high fructose consumption >>>> elevated triglycerides >>>> leptin resistance + high fructose consumption >>>> palmitic acid >>>> hypothalamic insulin resistance.
A diet full of sugar AND PUFAs AND palmitic acid causes cytokines to be expressed in the hypothalamus, activating the intracellular inflammatory signal transduction.
Research by Ono et al shows that hypothalamic insulin resistance precedes and probably causes insulin resistance in other organs and tissues (at least in rats). In a study by Obici et al central administration of insulin suppressed glucose production by the liver and blocked insulin signaling in the brain. That in turn impaired the ability of insulin to inhibit glucose production in the liver. So the majority of insulin’s ability to cause muscle to take up glucose is mediated by its effect on the brain. The hypothalamus is in charge of whether or not the body has an adequate energy intake by regulating energy stores and energy balancing hormones. In the case of leptin resistance the brain acts to restore homeostasis by signaling the peripheral metabolism to make more subcutaneous fat . When insulin signaling in the brain is impaired, the upkeep of homeostasis requires that more insulin be brought into the brain. To do this, the body must become hyperinsulinemic, so that enough insulin gets into the hypothalamus. The best way to accomplish this is to induce whole body insulin resistance, primarily in the liver and muscles. How does the insulin resistant brain manage to induce insulin resistance in the rest of the body? By growing intra-abdominal fat. Hypothalamic insulin resistance disrupts the hypothalamic-pituitary -adrenal axis, leading to increased secretion of ACTH and cortisol. These in turn stimulate the growth of intra-abdominal fat. That type of adipose tissue produces copious amounts of macrophages and releases pro-inflammatory cytokines and adipokines into the bloodstream. In the liver where they cause fatty liver, insulin resistance, and liver inflammation. Blood circulation carries these proinflammatory molecules to the muscles again causing insulin resistance and inflammation. So this is the way that the fat around your intestines ties in with whole body insulin resistance. Insulin resistance in the body causes the pancreas to go into overdrive to supply more insulin causing in hyperinsulimia >>> TYPE 2 DIABETES. So now the hypothalamus gets enough insulin. Once the inflammation in the arcuate nucleus in the brain is removed, and the NPY/AgRP neurons become more sensitive to insulin this response should stop and the situation return to normal.