We’re all familiar with the so-called weight loss drugs advertised on TV that claim unbelievable results, show before and after shots of what are clearly completely different people with unreasonable muscle development, and carry dangerous health side effects, but no FDA backing. But what if there were a way to nip weight gain in the bud by stopping fat cells from forming to begin with?
Scientists in New Jersey have developed just such a drug, assigned to Madrigal Pharmaceuticals in San Francisco. Rather than acting as an appetite suppressant like other weight loss pills, this pharmaceutical targets fat cell metabolism.
Here’s how it works. Triacylglycerols are the major form of energy storage in eukaryotic organisms (like humans). In mammals, these compounds are primarily synthesized in three tissues: small intestine, liver and adipocytes (aka, fat). They also support the major functions of fat absorption packaging of newly synthesized fatty acids and storage in fat tissue. Diaclyglycerol O-acyltransferase (DGAT) is a key enzyme in triglyceride synthesis, playing an essential role in the metabolism of cellular diacylglycerol. It is also critically important for triglyceride production and energy storage homeostasis.
DGAT activity levels increase in fat cells as they differentiate, and it has been discovered that DGAT may be regulated in adipose tissue post-transcriptionally. In the liver, the regulation of triglyceride synthesis is of primary importance in determining the rate of VLDL production (a type of lipoprotein that enables fats and cholesterol to move in the blood stream).
Two forms of DGAT have been cloned thus far – DGAT1 and DGAT2. The gene encoding for mouse DGAT1 has been used to create a DGAT knock-out. Knock-out mice that are unable to express a functional DGAT enzyme are still viable and continue to synthesize triglycerides. But, of great interest is that these mice are also resistant to diet-induced obesity, and remain lean even when fed a high-fat diet. In fact, they maintain comparable weights to those mice fed a diet with regular fat content.
Why are these knock-out mice staying thin? It turns out that mice unable to express functional DGAT have lower tissue triglyceride levels. Their resistance to weight gain is due to an increased energy expenditure and increased sensitivity to insulin and leptin. They have reduced rates of triglyceride absorption, improved triglyceride metabolism and improved glucose metabolism, with lower glucose and insulin levels following a glucose load as compared to wild-type mice.
Disorders and imbalances in triglyceride metabolism, both through absorption and synthesis, have been implicated in the pathogenesis of a variety of disease risks, including obesity, insulin resistance syndrome, type II diabetes, dyslipidemia, metabolic syndrome and coronary heart disease. Thus, compounds that can decrease triglyceride synthesis from diacytylglycerol by inhibiting or lowering the activity of the DGAT enzyme are of great value as therapeutic agents for treatment of these diseases.
DGAT inhibitors were already known in the art prior to this invention’s publication, but there remained a need for a DGAT inhibitor that has efficacy for treatment of metabolic disorders. This invention does just that.
Diet pills are dangerous and are unapproved by the FDA. Most often they contain dangerously high doses of caffeine that can raise the user’s heart rate to dangerous heights and cause dehydration, among other side effects. And the theory behind the pill is little more than appetite suppression. This invention instead uses good science to target the underlying causes for obesity, type II diabetes and other metabolic disorders -- triglyceride metabolism. In this way, this drug presents an innovative and potentially more reliable and safe solution for fighting against the obesity epidemic.
Beyond the mention of lean knock-out mice, the patent does not disclose any clinical trial testing or results. This means that it is in its very beginning stages as a pharmaceutical, and must progress through many testing phases before receiving FDA approval. The side effects are as yet unknown, and even the form the treatment will take is up in the air – the patent suggests that the compounds disclosed may be administered orally, sublingually, intravenously, rectally or by inhalation, in a single dose form or as continuous treatment. Bottom line? Don’t stop exercising and eating healthy just yet -- this wonder drug has a long ways to go.