I will now turn to an overview of the existing treatment available for treatment of obesity. Large scale genetic studies have revealed that the genes contributing to development of obesity is mainly located in the brain. For example, defects in the MC4 receptor, which has previously been mentioned, are contributing to development of obesity in more than 5% of all obese patients. Based on this it would be logical to try to target the brain when pursuing drugs for the treatment of obesity and develop drugs that "turn" the brain towards a lower body weight target - by decreasing appetite and increasing the metabolic rate. However, it is not that simple. The previous drugs on the market were to a large degree targeting the brain - but most of them were subsequently withdrawn from the market due to intolerable "side-effects". This is true for amphetamine, Fenfluramin/phenteramin, dexphenfluramin, and sibutramine, which are sympato-stimulatory drugs that increases metabolic drive and decrease food intake. But also true for rimonobant - that block the cannabinoid receptor - and the pleasure related to food intake. The observed side effects were cardiovascular failure for sympato-stimulatory drugs and suicide and depression for rimonobant. Drugs currently on the marked are Amferamon with a mechanism of action similar to that of sibutramin. It leads to blockage of mainly the NET but also to a lower degree a blockage of SERT and DAT - increasing the synaptic content of noradrenalin but also serotonin and dopamine. This drug is approved in Europe - but not approved by the FDA in the US. Lorcaserin has recently been approved on the marked by FDA for treatment of obesity for patients with severe obesity - a BMI more than 30 or comorbidity to the obesity. It is an agonist for the serotonin 2c receptor located on the inhibitory POMC neurons. Activation of these neurons leads to a mild decrease in food intake. Orlistat is a drug, which you can buy as an "over the counter" drug without prescription in low doses. For higher doses you need prescription from a doctor. It acts as an inhibitor of the pancreatic lipase that cleaves down the ingested triglycerids into the absorbable free fatty acids and monoacylglycerol. TG cannot be absorbed and will be excreted through the feces. The most commons side effect of this drug is frequent and oily feces that is difficult to control. Finally the last drug on the market has just recently been approved both in Europe and US is an analog of the GI tract peptide GLP1. This is one of the physiological satiety hormones that increases in response to a meal. Secretion of this hormone from the intestine will lead to increased glucose dependent insulin secretion from the pancreas and to a satiety signaling in the hypothalamus where it activate the inhibitory POMC neurons to decrease appetite and increase the metabolic rate. The problem is that native GLP-1 is degraded very fast so to prolong the plasma half life the endogenous peptide has to be modified. One type has been developed for the treatment of obesity obesity - called Saxenda. This drug is essentially the native GLP-modified by addition of a fatty acid . In summary most of the central acting treatments against obesity have been withdrawn from the marked, however in Europe we still have "Amphepramon" which primarily increases the synaptic content of noradrenalin. Lorcasarin an agonist on a specific type of serotonin receptors in hypothalamus is approved in U.S Olistat is a treatment that is available as over the counter drug - that act by decreasing the up take of fat from the diet. Finally a GLP-1 analog -Saxenda - has recently been approved as an anti obesity treatment mainly based on it effect in the hypothalamus. Basically none of the current treatment approaches are very efficient and without side effect. The most efficient treatment is bariatric surgery as described in previous lecture. In some of the approaches for future treatments in obesity and T2DM a -bariatric surgery drug is the ultimate goal. Today, it is known that after bariatric surgery food intake induces a release of GI tract derived satiety hormones that is much higher than if the undigested food reaches the stomach first. I will now introduce you to two different approaches based on secretion of satiety hormones from the GI tract in response to food intake. In one approach the drug is supposed to imitate a food item and activate the nutrient sensors - the previously mentioned 7TM receptors - and induce release of the whole package of hormones normally secreted by ingestion of food. In the other approach the drug is mimicking the GI tract hormone or a combination of hormones. This approach has already been used successfully by the GLP-1 analog just described. However, the new part is to administrate either a mixture of more than one peptide hormone or one peptide that possesses dual peptide properties. This means that the same peptide can bind and activate two different receptors with similar affinity. Drugs that artificially activate the same dietary sensors as fat have been pursued and some molecules have been tested in humans. When we eat fat it is almost always triglycerids we eat. The TG have to be cleaved down to long chained free fatty acids (LCFA) and monoacylglycerol (MG) in order to become absorbed by the enterocytes but it is also the LCFA and MG that activate the nutrient sensors that gives rise to secretion of satiety hormons. The LCFA are sensed by GPR40 and GPR120 whereas MG are sensed by GPR119. These nutritient sensors are expressed on the enteroendocrine cells and increases release of a package of hormones of fx GLP-1, GLP-2 and PYY. Future drugs could target only one of them or, ideally, a combination of these three receptors - but currently we do not know how they act together and what the most efficient approach is. Based on preliminary data, agonists targeting GPR119 - a sensor of MG and a fat metabolite OEA - gives a robust release of GLP-1 but also PYY and GLP-2 from the L-cells as shown here as well as GIP secretion from the K-cells. Several different pharmaceutical companies have successfully developed agonists targeting the GPR119 since this sensor seems to give the most efficient response in terms of hormone secretion (as seen here). However, many companies have over the last few years discontinued their drug discovery programs for this target; presumably due to unexpected and unacceptable side effects. Activation of one of the FFA sensors - gpr40 - is also highly promising in relation to drug development and secretion of high levels of GLP-1 and other satiety hormones - have been observed for agonist targeting this receptor. These data has encouraged drug discovery programs towards developing agonists specifically targeting the GPR40 - some of these programs have been initially successful and reached testing in clinical trials. One of the first compounds TAK-875 from TAKEDA induced improved glucose metabolism - shown as decrease in HbA1c. Further, when compared to one of the established oral antidiabetic drugs (glimpirid) it showed a reduced risk of hypoglycemic events. Unfortunately, also the clinical trials with this compounds has been discontinued due to liver toxicity, but other companies are still working on this target. This was just one example of using nutrient sensors as drug targets, but the pharmaceutical companies are also pursuing other sensors for protein and carbohydrates. A similar but different approach is to administrate more than one endogenous hormone or analogues of the endogenous hormones, in combination. We know today that for example GLP-1, GLP-2 and NTS are co-expressed, co-released and most likely also function together - in a Co-action. We have tried to co-administrate NTS together with a GLP-1 analog and found increased effects on gastric emptying as compared to administration of the individual hormones, respectively . Also the satiety effect of GLP-1 and NTS was enhanced by co-administration. Here it is shown for appetite for sweet drink. NTS on its own has no effect, and only a weak effect is shown for a low dose of the GLP-1 analog - but together, using the same doses as for the mono-components, they significantly decrease intake of the sweet drink. This shows that administering these two hormones together - as they are secreted under normal physiological conditions - will have a stronger effect than given alone. The last treatment approach is a co-administration of two hormones that conventionally would be expected to act oppositely - at least in terms of glucose metabolism. This concept is illustrated by co-administration of glucagon and GLP-1 - because these two peptides are structurally related it has been possible to design a peptide that acts through both of these two hormones receptors. Glucagon is mainly known as a hormone that counteracts low blood glucose by increasing the hepatic glucose production. This does not off hand sound like a hormone with beneficial effects for patients with T2DM and obesity. However, due to its profound effects on satiety and energy expenditure in the brain and its effect on adipocytes, glucagon agonists may in fact be beneficial treatment of diabetes, in particular if co-administered with a GLP-1 analogue. Administration of peptides designed to act both on the GLP-1 receptor and the glucagon receptor has been shown to have beneficial effect on obesity. As seen, the decrease in BW was further enhanced by the Co-agonist as compared to GLP-1 alone. Surprisingly, no un-wanted effects were observed on the glucose metabolism by administration of glucagon as seen by the fact that the improvement in glucose tolerance was equally good after treatment with the co-agonist as compared to GLP-1 analog alone. In conclusion it may be an efficient way to use pharmacological treatments that act in the brain, where the genetic studies indicate the disease is located - however these drugs are associated with severe side effect. I contrast stimulating the nutrient sensors - as the food components does after a meal, may be the safe way to the brain and future treatment of obesity.
