Colonic Propionate, Appetite, and Weight Loss
Condition: Healthy Obesity, Metabolically; Appetite Regulation
MeSH terms: Obesity, Metabolically Benign; Weight Loss
Study type: Interventional

Summary: 
      The current protocol aims to investigate the impact of the propionate ester in conjugation
      with restricted diet on appetite and weight loss.
    

Detailed description: 
      DIET AND OBESITY:

      Obesity has reached epidemic proportions worldwide. In the United Kingdom, 58% of adult women
      and 65% of adult men are either overweight or obese (Health and Social Care Information
      Centre 2014), with the expectation that rates will increase (Ng et al. 2014). Obesity, mainly
      caused by a chronic positive energy balance, is a known risk factor that contributes to the
      development of type 2 diabetes and cardiovascular diseases, and the subsequent morbidities
      and mortalities (Kopelman 2007). A positive energy balance is inevitable with the composition
      of current western diet that contain refined (fibre-depleted) carbohydrates that are consumed
      quickly, and have minimal effects on long-term satiety (Cleave 1974; Heaton 1973).

      NONDIGESTIBLE CARBOHYDRATES:

      The quality and quantity of diet has changed dramatically over the last fifty years. Of
      which, carbohydrates have the most significant changes; from unprocessed fruits and
      vegetables based carbohydrates to more processed cereal based ones (Cordain et al. 2005).
      Epidemiological studies have shown that, as a result, ancestral diets had greater amounts of
      Non-Digestible Carbohydrates (NDC) than modern diets (>100g/day compared to <15g/day) with
      the inclusion of more indigestible intact cell wall plant material, such as tubers, grasses
      and sedges (Eaton 2006). A strong association has been established between increased weight
      gain with decreased NDC intake (Liu et al. 2003). Furthermore, increasing intake of NDC have
      shown to induce satiety and improve body composition in animals (So et al. 2007) and humans
      (Bouché et al. 2002).

      LOW CALORIC HIGH NDC DIET IN LOSING WEIGHT Applying energy-restricted diets is one of the
      first steps to treat obesity. However, weight regain in weight maintenance period could
      happen due to resting energy expenditure reduction and lean mass loss. The inclusion of
      specific foods to the nutritional intervention is being investigated in order to produce
      persistent weight losses (Abete et al. 2008). It was suggested earlier that the addition of
      high fibre NDC foods to a hypocaloric diet would help reducing the incidence of metabolic
      syndrome and increasing the dietary compliance (Hermana et al, 2011). The high fibre content
      in combination with a low glycemic index diet, can both result in higher satiety effects with
      an increased mitochondrial oxidation, all favour weight loss.

      PROPIONATE AND THE FFAR2 RECEPTOR:

      Production of short chain fatty acids (SCFA) is the main by-product of NDC colonic
      fermentation (Pawlak et al. 2004). Of them, colonic propionate was found to play a critical
      role directly in the colon and systematically after its absorption into the circulation (Wong
      et al. 2006). Free Fatty Acid Receptor 2 (previously known as orphan G-coupled Protein
      Receptor 43) has been discovered to has high affinity to propionate (Brown et al. 2003). It
      is expressed on the distal ileum and colon L-enteroendocrine cells (Karaki et al. 2008),
      adipocytes and certain monocytes lineage (Hong et al. 2005).

      THE ROLE OF PROPIONATE IN GUT HORMONE RELEASE AND APPETITE REGULATION:

      The L-enteroendocrine colonic cells are responsible of secreting anorexic gut hormones (PYY
      and GLP-1) physiologically in response to food. These hormones are capable of inducing
      satiety through signalling the brain appetite centre (Murphy & Bloom 2006).
      Propionate-induced FFAR2 activation have found to cause the release of these hormones in
      vitro. Moreover, NDC ingestion was found to stimulate the release of these hormones in
      animals, resulting in decreasing food ingestion (Delzenne et al. 2005). Propionate was shown
      to replicate the same effects in further studies, suggesting the owning of the beneficial
      effects of NDC on appetite and gut hormones to propionate production.

      SHORT CHAIN FATTY ACID ESTER:

      Administering NDCs that promote the production of propionate is an attractive way to increase
      the level of propionate over an extended period of time. However, due to variability of the
      gut microbita activity, administering high proportions (≥ 35g/d) of dietary fibres in human
      diets to increase colonic propionate does not reliably or predictably provide the same SCFA
      levels in colon or systemically (Cummings 1981). Oral propionate supplementation is another
      method, but unfortunately its short plasma half-life, poor palatability, and the fact that
      its main absorption happens in the small intestine limit its use as a food supplement (Frost
      et al. 2003).

      A novel system has been developed by Dr Douglas Morrison, (Scottish Universities
      Environmental Research Centre (SUERC)). This molecule of inulin (β(2-1) linked polymer of
      fructose) carrier with an ester linked to propionate (propionate ester) was demonstrated to
      reliably and reproducibly increase colonic propionate while prevent the side effects of NDC
      (Chambers et al. 2015). Thus, propionate is only released when the carrier molecule inulin is
      fermented by colon microflora, which was estimated to be 180 minutes post-ingestion.
      (Chambers et al. 2014). Chambers et al. (2015) were able to show that 10g of
      Inulin-Propionate Esters (IPE) has the ability to deliver 2.4g of propionate to the colon,
      that is an increment of 2.5-fold of propionate production in the colon, a level that is
      achieved only with 60g/d via traditional dietary fibre supplementation. The same group has
      also demonstrated that while the acute administration of this supplement caused increments in
      Plasma GLP-1 and PYY and reduced food ingestion, the long term (24 weeks) supplementation of
      propionate ester significantly reduced body weight gain and the development of abdominal
      adipose tissue (Chambers et al. 2014). Interestingly, none of the long term participants
      reported any side effects from the intake of propionate esters. Increasing colonic propionate
      is, therefore, one of the attractive strategies to manage weight and diabetes risk factors.

      The current protocol aims to investigate the impact of the propionate ester in conjugation
      with restricted diet on appetite and weight loss.
    

Intervention name(s): Inulin-Propionate Esters; Inulin
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Inulin (β(2-1) linked polymer of fructose) carrier with an ester linked to propionate (propionate ester). Thus, propionate is only released when the carrier molecule inulin is fermented by colon microflora.; Inulin
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: double blind, randomised, controlled, paralleled study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: gut hormones; obesity; appetite; propionate; fermentation