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mHMGCS enzyme

mHMGCS enzyme inhibits signalling in small intestine

mHMGCS triggers the formation of ketone bodies in the intestinal mucous membrane that, in turn, dampen the GLP-1 release from the hormone-producing cells in response to meals

A previously unknown mechanism that suppresses satiety signals from the small intestine could explain, satiety disorders in patient with obesity and diabetes, and the prompt health effects of gastric bypass, according to Sahlgrenska Academy, University of Gothenburg, and Sahlgrenska University Hospital, Sweden. The researchers were seeking to answer the question of why, in patients who undergo gastric bypass surgery, there is a very rapid reversion from extremely low to normal levels of GLP-1 within days. The group's previous research shows that this change takes place within two days after the operation, long before the patients start losing weight.

The study, ‘Suppression of enteroendocrine cell glucagon-like peptide (GLP)-1 release by fat-induced small intestinal ketogenesis: a mechanism targeted by Roux-en-Y gastric bypass surgery but not by preoperative very-low-calorie diet’, published in Gut, is based on investigations of the small intestinal mucous membrane in post-operative gastric bypass patients, as well as in mice and cell cultures. The finding concerns a research field in which many scientists have long sought associations and mechanisms of the kind now presented.

The focus of the study is on the intestinal hormone glucagon-like peptide (GLP)-1, which belongs to a group of satiety hormones that are released from food sensitive hormone producing cells in the gastrointestinal mucous membrane when we eat. These hormones regulate appetite by signalling satiety to the brain in order to end meals and they increase secretion of insulin from the pancreas.

For reasons that are unclear, release of GLP-1 and other similar acting satiety-signalling hormones is inhibited in patients with obesity and type-2 diabetes, and this is considered to be a key causal mechanism underlying these disorders. Therefore, several modern medicines against diabetes and overweight copy, or mimic, GLP-1 in order to try to imitate the normal secretion of this substance.

The researchers found a mechanism in the small intestine that can explain how the satiety signalling is inhibited. The culprit is mHMGCS (mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase), an enzyme that triggers the formation of ketone bodies in the intestinal mucous membrane that, in turn, dampen the GLP-1 release from the hormone-producing cells in response to meals.

Mouse experimentation showed that the process was diet-dependent. Mice that were given a high-fat diet over a long period saw a massive rise in enzyme production. This was accompanied by increasing production of ketone bodies, which proved to suppress release of GLP-1 from the hormone-producing cells.

"Gastric bypass quite simply disconnects the part of the digestive system in which the problem, the ketone-body production, arises," explained Dr Ville Wallenius, associate professor and senior consultant in bariatric surgery and the principal author of the study. "After the operation, food enters directly from the oesophagus into the jejunum (the middle section of the small intestine) without passing the stomach and the duodenum. Then, when the food is no longer being mixed with bile and pancreatic enzymes that break down dietary fat into free fatty acids, that act as precursors for the ketone formation, the preconditions for the enzyme that triggers the ketone production simply disappear."

Schematic illustration of the proposed ketone body mechanism on GLP-1 producing enteroendocrine cells (EECs). Chronic free fatty acid (FFA) exposure induces increased mHMGCS expression and βHB production in jejunal epithelial cells in the villi tips. βHB reaches the EECs via the venous microcirculation of the villi, and acts via FFAR3/GPR41 to inhibit the production/release of GLP-1. RYGB surgery may interfere with this mechanism by decreasing FFA availability and mHMGCS expression. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLP-1, glucagon-like peptide-1; mHMGCS, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase; RYGB, Roux-en-Y gastric bypass.

"Ketone bodies are usually produced in the liver during starvation and are essential to our survival,” said Dr Lars Fändriks, a professor of bariatric surgery. “For example, during starvation, the brain is dependent on ketones as its primary energy source when it can't be met with glucose. Ketogenesis, the ketone production of the small intestine, seems to fulfil a completely different function.”

The researchers were seeking to answer the question of why, in patients who undergo gastric bypass surgery, there is a very rapid reversion from extremely low to normal levels of GLP-1 within days. The group's previous research shows that this change takes place within two days after the operation, long before the patients start losing weight.

“In summary, we suggest a surgical physiological reconstruction of the alimentary limb by inducing substrate deficiency for ketogenesis. This could contribute to the explanation of the very rapid improvement of incretin hormone secretion observed after RYGB, as we have recently shown is evident already two days after surgery,” the authors concluded in their paper. “These findings are consistent with the proposed ‘anti-incretin’ and ‘foregut exclusion’ hypotheses that could explain the effects of RYGB surgery on improved satiety and glucose homeostasis. This may open up a new avenue for the development of anti-obesity and anti-diabetic drugs, targeting mHMGCS and intestinal mucosal ketone production, in order to increase enteroendocrine cells responsiveness and gut peptide release on nutrient stimulation.

The scientists believe that these findings will open up for a new type of drugs. Instead of injecting copies of GLP-1, it might be possible to pharmacologically block the enzyme mHMGCS in the intestine. This would stop the suppression of the hormone-producing cells, which could thereby increase their release of both GLP-1 and other satiety hormones.

"That kind of drug could imitate the effect of the gastric bypass operation," concluded Ville Wallenius.

To access this paper, please click here

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