Asperuloside Improves Obesity and Type 2 Diabetes through Modulation of Gut Microbiota and Metabolic Signaling

Asperuloside (ASP) is an iridoid glycoside that is extracted from Eucommia leaves. Eucommia is used in traditional Chinese medicine and has a long history of benefits on health and longevity. Here, we investigated the impact of ASP on obesity-related metabolic disorders and show that ASP reduces body weight gain, glucose intolerance, and insulin resistance effectively in mice fed with a high-fat diet (HFD). Intestinal dysbiosis is closely linked with metabolic disorders. Our data indicate that ASP achieves these benefits on metabolic homeostasis by reversing HFD-induced gut dysbiosis and by changing gut-derived secondary metabolites and metabolic signaling. Our results indicate that ASP may be used to regulate gut microbiota for the treatment of obesity and type 2 diabetes.

The role of nicotinamide riboside kinases in mammalian NAD⁺ metabolism

Joanna Ratajczak

NAD+ has emerged as a central metabolic node and an important co-substrate for the activity of various enzymes, including the protein deacetylase SIRT1. Different strategies to increase NAD+ bioavailability have been shown to boost SIRT1 activity, which results in protection against metabolic disease, neurodegenerative disorders and certain types of cancer. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have recently been discovered as new NAD+ precursors. Recent studies have shown that dietary supplementation with NR or NMN prevented against high-fat diet-induced body weight gain. However, the physiological role of NR in mammalian metabolism remains largely unexplored. In this project, we focused on the first step of NR metabolism â the phosphorylation of NR by nicotinamide riboside kinases (NRK1 and NRK2). We have investigated the role of NRKs in the metabolism of NAD+ precursors and mammalian physiology in vivo. The results obtained indicate that NRKs are the rate-limiting and essential step for NR- and NMN-driven NAD+ synthesis in hepatocytes and that NMN has to be extracellularly converted to NR for its use as an NAD+ precursor. Accordingly, animals lacking NRK1 have defects in NR/NMN utilization. We demonstrated that effective NR utilization is key for the maintenance of metabolic homeostasis as NRK1 whole-body KO mice display numerous alterations in glucose and lipid management. Using NRK1 liver-specific KO mice, we demonstrate that NRK1 is required to maintain hepatic NAD+ levels and mitochondrial function upon high-fat feeding. Consequently, NRK1LKO mice are sensitized to diet-induced glucose intolerance and insulin resistance. Finally, we show that both isoforms of NRK are redundant in mediating NR/NMN effects in muscle. Hence, this work identifies NRKs as a novel valuable target in the fight against metabolic disease and indicates that the regulation of NRK will enable us to find novel ways of enhancing NAD+ availability. Moreover, it has unveiled a critical role of NRK1 for the metabolism of diverse forms of Vitamin B3 and highlights how circulating NR is key to preserve metabolic health upon dietary challenges.

EPFL2017

Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure

Johan Auwerx, Chikage Mataki, Kristina Schoonjans

We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome.

2011

Enhanced activation of cellular AMPK by dual-small molecule treatment: AICAR and A769662

Laurent Bultot, Maria Deak, Kei Sakamoto

AMP-activated protein kinase (AMPK) is a key cellular energy sensor and regulator of metabolic homeostasis. Activation of AMPK provides beneficial outcomes in fighting against metabolic disorders such as insulin resistance and type 2 diabetes. Currently, there is no allosteric AMPK activator available for the treatment of metabolic diseases, and limited compounds are available to robustly stimulate cellular/tissue AMPK in a specific manner. Here we investigated whether simultaneous administration of two different pharmacological AMPK activators, which bind and act on different sites, would result in an additive or synergistic effect on AMPK and its downstream signaling and physiological events in intact cells. We observed that cotreating primary hepatocytes with the AMP mimetic 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and a low dose (1 mu M) of the allosteric activator A769662 produced a synergistic effect on AMPK Thr172 phosphorylation and catalytic activity, which was associated with a more profound increase/decrease in phosphorylation of downstream AMPK targets and inhibition of hepatic lipogenesis compared with single-compound treatment. Mechanistically, we found that co-treatment does not stimulate LKB1, upstream kinase for AMPK, but it protects against dephosphorylation of Thr172 phosphorylation by protein phosphatase PP2C alpha in an additive manner in a cell-free assay. Collectively, we demonstrate that AICAR sensitizes the effect of A769662 and promotes AMPK activity and its downstream events. The study demonstrates the feasibility of promoting AMPK activity by using two activators with distinct modes of action in order to achieve a greater activation of AMPK and downstream signaling.

Amer Physiological Soc2014

The role of nicotinamide riboside kinases in mammalian NAD⁺ metabolism

Joanna Ratajczak

EPFL2017