A long term solution to the obesity epidemic remains elusive.  However, dietary supplements are commonly marketed to the consumer with claims to promote and maintain weight loss.  For example, pregnane glycoside-enriched extracts (proposed to have appetite suppressing effects) from a desert milkweed plant Hoodia are among the most popular botanical weight-loss remedies despite the lack of pre-clinical and toxicological research evidence.  It is not clear how Hoodia is effective in causing weight loss, and the site and mode of action for pregnane glycosides in regulating food intake or energy balance have yet to be determined.

To validate the physiological and pharmacological effects of pregnane glycoside-enriched botanicals, we screened plants that belong to the milkweed family and identified swamp milkweed, Asclepias incarnate, a common and fast growing North American relative of Hoodia, as an alternative source of active ingredients.  In collaboration with Botanical Research Center investigators during the initial funding cycle, we showed that roots of A. incarnate provide a reproducible, abundant and readily available source of these compounds for research and therapeutic applications.  The appetite suppression activity of crude extract of A. incarnata roots enriched with pregnane glycosides (incarnatin) was demonstrated in rats and mice.  A. incarnata extract produced an acute reduction in food intake that reduced fat deposition and improved markers of insulin sensitivity, possibly through a mechanism requiring gut-brain communication via primary vagal afferents.  Studies involving chronic treatment with the extract and pair feeding to control for its effect on food intake supported an additional metabolic role of the extract independent of its effects on food intake.  Incarnatin treatment was also associated with favorable changes in expression of an orexigenic agouti gene-related protein (AgRP) in the hypothalamus.  Based on these observations, we hypothesize that incarnatin impacts energy homeostasis by promoting satiety and stimulating energy expenditure.  Thus our primary goal is to understand the complementary components of the mechanism by which this botanical enhances satiety and attenuates the progression to metabolic syndrome.  We will achieve this goal through a set of three specific aims as follows. 

Specific Aims

• To identify the mechanism(s) of the anorexigenic effects of incarnatin. Our hypothesis predicts that incarnatin extract acutely reduces food intake and delays gastric emptying through an enteroendocrine signaling mechanism involving vagal communication to the brainstem and/or hypothalamus.
• To identify the mechanism(s)of energy expenditure in the anti-obesity activity of incarnatin. Our hypothesis predicts that incarnatin stimulates energy expenditure through favorable effects on uncoupling proteins and adiponectin levels, therefore improving overall energy blance and insulin sensitivity.
• To identify the bioavailability and structure-activity properties of incarnatin and its bioactives. Our hypothesis predicts that biological activity of incarnatin and its active principles is affected by bioavailability and will correlate with in vivo activity of incarnatin in cell culture asays.