Evaluation of Botanicals for Mechanisms Related to Appetite and Fat Metabolism
Condition: Overweight; Obesity
MeSH terms: Overweight
Study type: Interventional

Summary: 
      Excess caloric consumption, particularly from inexpensive, energy dense foods that are high
      in fat and refined carbohydrates, is a major driver of the global obesity epidemic. Dietary
      supplements that promote reduced intake of energy dense foods and/or impact the absorption
      and metabolism of fat and carbohydrates in the body can be used to help consumers control
      their weight. We identified two separate mechanistic approaches to target these effects.

      Diacylglycerol acyltransferase-1 (DGAT-1) is an enzyme involved in the formation of dietary
      fat into circulating triglycerides within the body. Once dietary fat is digested and
      absorbed, the resulting fatty acids are re-esterified into triglycerides. Inhibition of
      DGAT-1 results in delayed and decreased re-esterification of dietary fats into circulating
      triglycerides. It is hypothesized that this effect may lead to decreased deposition of excess
      dietary fat as adipose tissue, possibly due to increased fatty acid oxidation in the
      enterocytes.

      Ghrelin is a hormone that is known to stimulate appetite in humans. When calorie dense fatty
      foods are sensed in the stomach, ghrelin is acylated and activated via ghrelin
      O-acyltransferase (GOAT). The activation step attaches a medium chain fatty acid to the
      ghrelin molecule that enables it to transmit a signal in the brain that triggers eating and
      fat storage in adipose tissue. Interfering with the GOAT pathway will inhibit ghrelin
      activation and possibly diminish food intake and lipid storage. This concept is supported by
      animal studies in which weight gain in a high fat diet model is prevented when GOAT is
      inhibited.

      Our objective was to determine whether botanicals demonstrating in vitro DGAT-1 and GOAT
      inhibition have similar mechanistic effects in the human body. Based on the results of this
      study, prototype formulas may be developed and clinically- tested for outcomes related to
      weight management.
    

Detailed description: 
      Excess caloric consumption, particularly from inexpensive, energy dense foods that are high
      in fat and refined carbohydrates, is a major driver of the global obesity epidemic. Dietary
      supplements that promote reduced intake of energy dense foods and/or impact the absorption
      and metabolism of fat and carbohydrates in the body can be used to help consumers control
      their weight. We identified two separate mechanistic approaches to target these effects.

      Diacylglycerol acyltransferase-1 (DGAT-1) is an enzyme involved in the formation of dietary
      fat into circulating triglycerides within the body. Once dietary fat is digested and
      absorbed, the resulting fatty acids are re-esterified into triglycerides. Inhibition of
      DGAT-1 results in delayed and decreased re-esterification of dietary fats into circulating
      triglycerides. It is hypothesized that this effect may lead to decreased deposition of excess
      dietary fat as adipose tissue, possibly due to increased fatty acid oxidation in the
      enterocytes.

      Ghrelin is a hormone that is known to stimulate appetite in humans. When calorie dense fatty
      foods are sensed in the stomach, ghrelin is acylated and activated via ghrelin
      O-acyltransferase (GOAT). The activation step attaches a medium chain fatty acid to the
      ghrelin molecule that enables it to transmit a signal in the brain that triggers eating and
      fat storage in adipose tissue. Interfering with the GOAT pathway will inhibit ghrelin
      activation and possibly diminish food intake and lipid storage. This concept is supported by
      animal studies in which weight gain in a high fat diet model is prevented when GOAT is
      inhibited.

      Ghrelin levels are positively associated with stress, sleep deprivation, and caloric
      restriction. Weight loss induced by exercise does not have the same positive association with
      ghrelin levels that caloric restriction alone has. Ghrelin levels are influenced by diet
      composition, however, the results vary considerably between trials.

      Over 160 botanical extracts from our internal ingredient library were screened at a single
      concentration for inhibition of both DGAT-1 and GOAT. Botanicals that were identified as
      having at least 75% activity were then titrated to identify those with IC50 values < 25 g/ml
      or less. We narrowed our list of viable ingredients by looking at those with activity in both
      the DGAT-1 and GOAT in vitro enzyme bioassay models. The top performing botanicals were then
      evaluated in a cellular model for DGAT-1 inhibition. Those with the highest inhibition
      activity in this model were considered lead candidates. A preliminary literature search was
      conducted and the final filter included factors such as cost and regulatory acceptability
      which results in the four ingredients being tested in the current clinical protocol.Our
      objective was to determine whether these four ingredients have similar mechanistic effects in
      the human body.
    

Intervention name(s): Placebo; Apple; Grape; Raspberry; Apricot/Nectarine
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): Participants were randomly assigned to receive one of four botanical interventions or placebo.; Participants were randomly assigned to receive one of four botanical interventions or placebo.; Participants were randomly assigned to receive one of four botanical interventions or placebo.; Participants were randomly assigned to receive one of four botanical interventions or placebo.; Participants were randomly assigned to receive one of four botanical interventions or placebo.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment