AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which — in diet-induced obese mice — increased glucose uptake in skeletal muscle, reduced β cell stress, and promoted β cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro- and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.

Ketogenic low-carbohydrate high-fat (LCHF) diets are popular among young, healthy, normal-weight individuals for various reasons. We aimed to investigate the effect of a ketogenic LCHF diet on low-density lipoprotein (LDL) cholesterol (primary outcome), LDL cholesterol subfractions and conventional cardiovascular risk factors in the blood of healthy, young, and normal-weight women. The study was a randomized, controlled, feeding trial with crossover design. Twenty-four women were assigned to a 4 week ketogenic LCHF diet (4% carbohydrates; 77% fat; 19% protein) followed by a 4 week National Food Agency recommended control diet (44% carbohydrates; 33% fat; 19% protein), or the reverse sequence due to the crossover design. Treatment periods were separated by a 15 week washout period. Seventeen women completed the study and treatment effects were evaluated using mixed models. The LCHF diet increased LDL cholesterol in every woman with a treatment effect of 1.82 mM (p < 0.001). In addition, Apolipoprotein B-100 (ApoB), small, dense LDL cholesterol as well as large, buoyant LDL cholesterol increased (p < 0.001, p < 0.01, and p < 0.001, respectively). The data suggest that feeding healthy, young, normal-weight women a ketogenic LCHF diet induces a deleterious blood lipid profile. The elevated LDL cholesterol should be a cause for concern in young, healthy, normal-weight women following this kind of LCHF diet.

Excess body fat is a major health issue and a risk factor for the development of numerous chronic diseases. Low-carbohydrate diets like the Atkins Diet are popular for rapid weight loss, but the long-term consequences remain the subject of debate. The Scandinavian low-carbohydrate high-fat (LCHF) diet, which has been popular in Scandinavian countries for about a decade, has very low carbohydrate content (~5 E %) but is rich in fat and includes a high proportion of saturated fatty acids. Here we investigated the metabolic and physiological consequences of a diet with a macronutrient composition similar to the Scandinavian LCHF diet and its effects on the organs, tissues, and metabolism of weight stable mice. Female C57BL/6J mice were iso-energetically pair-fed for 4 weeks with standard chow or a LCHF diet. We measured body composition using echo MRI and the aerobic capacity before and after 2 and 4 weeks on diet. Cardiac function was assessed by echocardiography before and after 4 weeks on diet. The metabolic rate was measured by indirect calorimetry the fourth week of the diet. Mice were sacrificed after 4 weeks and the organ weight, triglyceride levels, and blood chemistry were analyzed, and the expression of key ketogenic, metabolic, hormonal, and inflammation genes were measured in the heart, liver, and adipose tissue depots of the mice using real-time PCR. The increase in body weight of mice fed a LCHF diet was similar to that in controls. However, while control mice maintained their body composition throughout the study, LCHF mice gained fat mass at the expense of lean mass after 2 weeks. The LCHF diet increased cardiac triglyceride content, impaired cardiac function, and reduced aerobic capacity. It also induced pronounced alterations in gene expression and substrate metabolism, indicating a unique metabolic state. Pair-fed mice eating LCHF increased their percentage of body fat at the expense of lean mass already after 2 weeks, and after 4 weeks the function of the heart deteriorated. These findings highlight the urgent need to investigate the effects of a LCHF diet on health parameters in humans.

Age is associated with progressively impaired, metabolic, cardiac and vascular function, as well as reduced work/exercise capacity, mobility, and hence quality of life. Exercise exhibit positive effects on age-related dysfunctions and diseases. However, for a variety of reasons many aged individuals are unable to engage in regular physical activity, making the development of pharmacological treatments that mimics the beneficial effects of exercise highly desirable. Here we show that the pan-AMPK activator O304, which is well tolerated in humans, prevented and reverted age-associated hyperinsulinemia and insulin resistance, and improved cardiac function and exercise capacity in aged mice. These results provide preclinical evidence that O304 mimics the beneficial effects of exercise. Thus, as an exercise mimetic in clinical development, AMPK activator O304 holds great potential to mitigate metabolic dysfunction, and to improve cardiac function and exercise capacity, and hence quality of life in aged individuals.