Method Of Treatment Of Obesity

Abstract

The present invention provides compositions and pharmaceutical compositions of GPR84 agonists and GPR120 agonists for us in the treatment of obesity and overweight. The invention provides methods of treatment accordingly as well as a kit for use in the treatment of obesity and overweight.

Claims

1. A method of treating obesity and overweight comprising administering to a subject in need thereof a composition comprising a GPR84 agonist and a GPR120 agonist.

2. A method as claimed in claim 1, wherein the GPR84 agonist is (a) a free fatty acid (FFA) with carbon chain length of C9 to C14 selected from the group consisting of lauric acid (C12:0), pelargonic acid (C9:0), capric acid (C10:0), undecanoic acid (C11:0); tridecanoic acid (C13:0) and myristic acid (C14:0), or an ester thereof, or (b) pentylthiopyrimidine-4,6-diol, 6-nonylpyridine-2,4-diol, embelin (undecyl-1,4-benzoquinone) or an ester thereof, or 3,3′-diindolylmethane.

3. A method as claimed in claim 2, wherein GPR84 agonist is a free fatty acid (FFA) selected from the group consisting of lauric acid (C12:0), undecanoic acid (C11:0) and capric acid (C10:0), or an ester thereof.

4. A method as claimed in claim 3, wherein the GPR84 agonist is lauric acid, or an ester thereof.

5. A method as claimed in claim 1, wherein the GPR120 agonist is an omega-3 fatty acid or an analogue thereof, or an ester thereof.

6. A method as claimed in claim 5, wherein the omega-3 fatty acid is selected from the group consisting of α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), or an ester thereof.

7. A method as claimed in claim 5, wherein the omega-3 fatty acid analogue is selected from the group consisting of [3-(4-((4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoic acid (TUG891) 4-Methoxy-N-(2,4,6-trimethylphenyl)benzenesulfonamide, 4-(4-{2-[phenyl(pyridin-2-yl)amino]ethoxy}phenyl) butanoic acid, and grifolic acid, or an ester thereof.

8. A method as claimed in claim 1, in which the GPR120 agonist is from a natural source.

9. A method as claimed in claim 8, in which the natural source of GPR120 agonist is a plant seed oil.

10. A method as claimed in claim 9, in which the plant seed oil is linseed oil.

11. A method as claimed in in claim 1, wherein the composition further comprises an amino acid.

12-13. (canceled)

14. A method as claimed in claim 1, wherein the composition is a delayed release formulation for release in the distal small intestine and large intestine.

15-19. (canceled)

20. A method as claimed in claim 1, wherein the composition comprises a pair of GPR84 agonists and a GPR120 agonist.

21. A method as claimed in claim 20, wherein the pair of GPR84 agonists is lauric acid and 3,3′-diindolylmethane and the GPR120 agonist is α-linolenic acid.

22. A method as claimed in claim 1, wherein the composition is administered orally.

23. A method as claimed in claim 14, wherein the delayed release formulation is a delayed release capsule.

24. A method as claimed in claim 1, wherein the composition is administered rectally.

25. A method as claimed in claim 24, wherein the composition is a suppository.

Description

[0083] The invention will now be further described by way of illustration with reference to the following Examples and drawings in which:

[0084] FIG. 1 shows L-cells co-express GPR120 and GPR84.

[0085] FIG. 2 shows Enterochromaffin cells co-express GPR120 and GPR84.

[0086] FIG. 3 shows GPR84 and GPR120 are predominantly expressed on 5-HT containing EC cells alongside L-cells albeit to a lesser extent.

[0087] FIG. 4 shows Top panel—TUG891 significantly increases cellular activation as measured by expression of pCAMKII at 10 μM compared to control (N=3, p<0.05). Bottom panel—5-HT positive cells are activated following stimulation with TUG891 as shown by merge image.

[0088] FIG. 5 shows stimulating human proximal colon with a combination of LA and TUG891 significantly increased the activation of both pERK and pCamKII suggesting increased overall activation of colonic epithelial cells. (N=3, n=15, p<0.05).

[0089] FIG. 6 shows synergistic effect of compositions of the invention (a) cell activation by Lauric Acid (LA) alone when administered at 12.5 mmol.sup.−1 and 25 mmol.sup.−1 compared to a control; (b) TUG891 alone when administered at 1 μM and 10 μM compared to a control; and (c) LA plus TUG891 in combination (25 mmol.sup.−1 LA and 10 μM TUG891) compared to a control and LA at 25 mmol.sup.−1 or TUG891 at 10 μM when administered alone.

[0090] FIG. 7 shows hormone release profile from cells of PYY and GLP-1 for compositions of the invention using Lauric Acid (LA) and TUG891 (TUG).

[0091] FIG. 8 shows GPR84 agonist 3,3′-diindolylmethane (DIM) potently activates pERK in combination with GPR120 agonist TUG891 and GPR84 agonist lauric acid.

[0092] FIG. 9 shows naturally occurring GPR120 agonists α-linolenic acid (ALA) and linseed oil potently induce expression of cell activation markers pCamKii and pERK in human colonic mucosa. (a) Both ALA and linseed oil activate coloncytes via pCamKii activation, with majority of positive staining in the apical region of the cell. Arrows point to positive cell highlighted in magnified inset image. (b) A large number of colonocytes are positive for pERK as shown by the white stars when stimulated with ALA and linseed oil.

EXAMPLE 1

[0093] Co-Expression of Nutrient Receptors GPR120 and GPR84 on L-Cells (Containing GLP-1) and Enterochromaffin Cells (Containing 5-HT)

[0094] The co-expression of nutrient receptors GPR120 and GPR84 on L-cells (containing GLP-1) and enterochromaffin cells (containing 5-HT) was examined using triple staining immunohistochemistry on human proximal colon. FIG. 1 demonstrates that both receptors are expressed on the basal side of L-cells (red). FIG. 2 shows enterochromaffin cells (green) express both receptors all around the cell, including the long process that extends into the lumen and has direct contact with luminally available nutrients. It was found that both GPR84 and GPR120 were highly expressed in 5-HT containing enterochromaffin cells (EC) in addition to being expressed on L-cells (with GLP-1 and PYY) (FIG. 3).

EXAMPLE 2

[0095] GPR120 Agonist Preferentially Activates a Different Intracellular Pathway Driven by Phosphorylated CaMKII

[0096] Previously it has been shown (Symonds, Peiris, et al, Gut 2014) that stimulation of human colonic mucosa with lauric acid (GPR84 agonist) activates an intracellular pathway as measured by phosphorylated ERK. The present results show TUG891 (GPR120 agonist) preferentially activates a different intracellular pathway driven by phosphorylated CaMKII, with some activated cells identified as EC cells (FIG. 4).

EXAMPLE 3

[0097] Combination Formulation for Activation of L-Cells and EC Cells in Human Proximal Colonic Sheets

[0098] The present results also show that both pERK and pCaMKII are up-regulated demonstrating that a combination of nutrients is able to increase the number of activated cells compared to a single nutrient treatment (FIG. 6). Importantly, increased numbers of activated L-cells are able to maximally release their contents, the hormones GLP-1 and PYY when stimulated by a combination formula i.e. lauric acid and TUG891, in human proximal colonic sheets (FIG. 7).

EXAMPLE 4

[0099] Patient Trials of Formulations

[0100] The compositions of the invention are to be tested in patients in the following scheme. [0101] 1.sup.st stage acute [0102] Objective: to test efficacy of modified release capsule of combination nutrients on metabolic parameters in obese type 2 diabetics [0103] Design: Randomised Double-blind Placebo-controlled Crossover of 20 overweight volunteers. (1 g, 2 g and 5 g dosage, 60 min before 2 standard meals 4 hr apart, 2 weeks between trials) [0104] Outcomes: [0105] postprandial satiety questionnaire, plasma gut hormone, 5-HT, glucose and insulin profile [0106] 2.sup.nd stage chronic [0107] Type: Phase lib. [0108] Objective: to test efficacy of modified release capsule of combination nutrients on weight loss and glycemic control [0109] Design: Randomised Double-blind Placebo-controlled Parallel Pilot trial with 20 overweight volunteers. (Dosage will be based on data obtained from stage 1 trial, 60 min pre-prandial b.i.d.). No run-in orwash-out [0110] Outcomes: [0111] 1°—Weight loss over 24 week administration [0112] 2°—Body fat mass, glycated haemoglobin (HbA1c), fasting blood glucose concentration (BGC).

EXAMPLE 5

[0113] GPR84 Agonist 3,3′-Diindolylmethane (DIM) Potently Activates pERK in Combination with GPR120 Agonist TUG891 and GPR84 Agonist Lauric Acid.

[0114] The results show GPR84 agonist 3,3′-diindolylmethane (DIM) potently activates an intracellular pathway driven by phosphorylated ERK in colonocytes, when administered in combination with GPR120 agonist TUG891 and GPR84 agonist lauric acid (FIG. 8).

EXAMPLE 6

[0115] 100 mM ALA and Linseed Oil Activate Intracellular Pathways Driven by Phosphorylated ERK and Phosphorylated CaMKII.

[0116] Naturally occurring GPR120 agonists ALA and Linseed oil activate intracellular pathways as measured by both phosphorylated ERK and phosphorylated CaMKII in human colonic mucosa. ALA and Linseed oil have a high affinity for GPR120 but are also recognised by GPR84. ALA and Linseed oil activate both phosphorylated ERK and phosphorylated CaMKII in comparison to the selective GPR120 agonist TUG891 which only activates phosphorylated CaMKII (see Example 2) (FIG. 8).