A Synthetic ERR Agonist Alleviates Metabolic Syndrome

Abstract

Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α, β, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.

Fig. 1.

SLU-PP-332 improves muscle function and increases fatty acid metabolism in vivo. Results from a 28-day SLU-PP-332 dosing regimen in C57Bl6 mice on a normal chow diet. Mice were kept at thermoneutrality and also assessed in CLAMS. Body weight (A), fat mass gain (B), blood lipid profile (C) (total cholesterol, high-density lipoprotein, and TG), and liver enzymes (D) of 3-month-old males treated with vehicle (white bar, n = 8) or SLU-PP-332 (black bar, n = 8) for 28 days. Results from the CLAMS of the same animals treated with vehicle (white bar, n = 8) and SLU-PP-332 (black bar, n = 8) under chow diet during the day (solid bar) and night (shaded bar) over the 5 days at thermoneutrality are illustrated in (E) through (J). Locomotor activity (E); RER [(F) and (G)]; fatty acid oxidation (H); carbohydrate oxidation (I) in these mice is illustrated. Energy expenditure (J) and average food consumption (K) over the 28 days from the same mice. In (F) arrow points to the first dosing. (L), Hematoxylin and Eosin staining of WAT from vehicle (left) or SLU-PP-332 (right) treated animals (n = 4) and quantitation of adipocytes size. * P < 0.05, ** P < 0.01, ***P < 0.001, ****P < 0.0001.

Fig. 2.

SLU-PP-332 does not improve glucose metabolism in vivo in chow-fed mice. Fed and fasted blood glucose levels (A) of the animals treated with vehicle (white bar, n = 8) and SLU-PP-332 (black bar, n = 8) maintained on a chow diet (fed) or after 8 hours of fasting (fast). Blood insulin level (B) of the animals treated with vehicle (white bar, n = 8) and SLU-PP-332 (black bar, n = 8) under chow diet (fed) after 28 days of treatment. Intraperitoneal glucose (C) and pyruvate (D) tolerance tests from vehicle (open circle/white bar) or SLU-PP-332 (black square/bar) treated animal (n = 8/group) under chow diet. The area under the curve is represented on each graph. (E) Hematoxylin and Eosin staining of the pancreas from vehicle (left) or SLU-PP-332 (right) treated animals (n = 4). Muscle pyruvate (F) and glycogen (G) content from animals treated with vehicle (white bar, n = 8) and SLU-PP-332 (black bar, n = 8) under chow diet (fed) after 28 days of treatment. (H) In vivo muscle glucose uptake from vehicle (white bar, n = 4) or SLU-PP-332 (black bar, n = 4) treated mice for 15 days.

Fig. 3.

SLU-PP-332 increases fatty acid metabolism in a DIO mouse model. Body weight (A), fat mass gain (B), blood lipid profile (C) (total cholesterol, high-density lipoprotein, low-density lipoprotein, and TG), and liver enzymes (D) of DIO males treated with vehicle (gray bar, n = 7) or SLU-PP-332 (black bar, n = 7) for 28 days. Mice were kept at thermoneutrality and fed with an HFD. Blood glucose (E) and insulin (F) levels of animals treated with vehicle (gray bar, n = 7) and SLU-PP-332 (black bar, n = 7) under HFD (fed) or after 8 hours of fasting (fast). Only fasting insulin levels are shown. (G–L) Indirect calorimetry measurement from the same animals treated with vehicle (gray bar, n = 7) and SLU-PP-332 (black bar, n = 7) during the day (solid bar) and night (shaded bar) over 5 days. RER (G); fatty acid oxidation (H); carbohydrate oxidation (I), activity and (J), and energy expenditure (K). (L) Energy expenditure difference between before and after dosing normalized by food intake and body weight from the same animals. Glucose tolerance test (M) from the same animals treated with vehicle (gray bar, n = 7) and SLU-PP-332 (black bar, n = 7) maintained on an HFD. The area under the curve for the glucose tolerance test is also shown. WAT (N) from mice dosed with vehicle (gray bars, n = 7) or SLU-PP-332 (black bar, n = 7) maintained on an HFD. The bar graph represents the average size of adipocytes (vehicle: white and SLU-PP-332: black bar). Liver from these mice stained with Oil Red O (O) and liver triglyceride (P) content from mice administered vehicle (gray bars, n = 7) or SLU-PP-332 (black bar, n = 7) under HFD. (Q) Liver gene expression from mice under chow diet (solid bar, n = 8) or fed with HFD (striped bar, n = 7), treated with vehicle (white bar) or SLU-PP-332 (black bar) for 28 days.* P < 0.05, ** P < 0.01, ***P < 0.001, ****P < 0.0001.

Fig. 4.

SLU-PP-332 increases fatty acid metabolism and energy expenditure in ob/ob mice. Body weight (A), fat mass (B), liver weight (C), and daily food intake (D) of 3-month-old ob/ob male mice treated with vehicle (white bar, n = 8) or SLU-PP-332 (black bar, n = 8) for 15 days. Mice were maintained at thermoneutrality and fed a chow diet. Results from indirect calorimetry (E), RER (F), fatty acid oxidation (G), carbohydrates oxidation (H), resting energy expenditure (I) of the same animals treated with vehicle (white bar, n = 8), and SLU-PP-332 (black bar, n = 8) maintained on an HFD during day and night over 15 days at thermoneutrality. Liver histology (J) Hematoxylin and Eosin and Oil Red O staining of frozen liver sections from mice treated with vehicle or SLU-PP-332 for 15 days. * P < 0.05, **P < 0.01, ***P < 0.001.