Obesity is a condition where storage of excess body fat results in adverse health effects such as increased risks of diabetes, stroke etc. Available treatment options include Prescription weight-loss drugs that work on CNS and suppress hunger ( Lorcaserin), block absorption and digestion of fat (Orlistat )  etc. all of which cause an arsenal of side-effects and/or surgery for removal of excess fat which is highly invasive. An alternative treatment approach is to regulate the cellular differentiation where precursors of fat cells (known as preadipocytes) convert to fat cells (adipocytes) capable of storing excess fat (called adipogenesis). There are several small molecules such as resistin, retinoic acid, resveratrol etc. that have been shown to inhibit adipogenesis and are currently in preliminary research.  Of these molecules, resveratrol (3,5,4'-tehydroxy-trans-stilbene), a natural product found in red grapes,  has advanced into pre-clinical trials for anti-obesity indications. However, initial pre-clinical studies of resveratrol report a low bioavailability making therapeutic dosage impractical for physiological effects. We designed and synthesized two-methoxy derivatives of resveratrol, MC4 (3,4,5,4'-tetramethoxy-cis-stilbene) and MR4 (3,4,5,4'-tetramethoxy-trans-stilbene)  that circumvent the low bioavailability issue of resveratrol due to protective methoxy groups.  In this study we evaluated the role of resveratrol and its methoxy analogs (MC4 & MR4), in adipogenesis using in-vitro obesity models (3T3-L1 and 3T3-F442A cell lines). It was determined that both of these analogs (MC4 & MR4) inhibited fat accumulation much similar to the inhibitory effect of resveratrol, but at a much lower dose (MC4 10nM) and MR4 (5uM). The findings of this study indicate a biosimilar role for the potent and novel analogs of resveratrol, MC4 and MR4 in adipogenesis and offer potential for therapeutics in obesity.

Effect of potent analogs of resveratrol, MC4, and MR4 on preadipocyte differentiation

247th National Meeting (2014)

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