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GDF15 mediates the effects of metformin on body weight and energy balance
Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk
1
,
2
. More than 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner
3
. The molecular mechanisms by which metformin lowers body weight are unknown. Here we show—in two independent randomized controlled clinical trials—that metformin increases circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15), which has been shown to reduce food intake and lower body weight through a brain-stem-restricted receptor. In wild-type mice, oral metformin increased circulating GDF15, with
GDF15
expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GDNF family receptor α-like (GFRAL). In obese mice on a high-fat diet, the effects of metformin to reduce body weight were reversed by a GFRAL-antagonist antibody. Metformin had effects on both energy intake and energy expenditure that were dependent on GDF15, but retained its ability to lower circulating glucose levels in the absence of GDF15 activity. In summary, metformin elevates circulating levels of GDF15, which is necessary to obtain its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.
In mouse studies, metformin treatment results in increased secretion of growth/differentiation factor 15 (GDF15), which prevents weight gain in response to high-fat diet, and GDF15-independent lowering of circulating blood glucose.
Journal Article
Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise
Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased
Gdf15
expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.
The physiological role of GDF15 remains poorly defined. Here, the authors show that circulating GDF15 increases in response to prolonged exercise, but that this exercise-induced GDF15, unlike pharmacological GDF15, does not affect post-exercise food intake or exercise motivation.
Journal Article
Metabolite Profiling Identifies a Key Role for Glycine in Rapid Cancer Cell Proliferation
Metabolic reprogramming has been proposed to be a hallmark of cancer, yet a systematic characterization of the metabolic pathways active in transformed cells is currently lacking. Using mass spectrometry, we measured the consumption and release (CORE) profiles of 219 metabolites from media across the NCI-60 cancer cell lines, and integrated these data with a preexisting atlas of gene expression. This analysis identified glycine consumption and expression of the mitochondrial glycine biosynthetic pathway as strongly correlated with rates of proliferation across cancer cells. Antagonizing glycine uptake and its mitochondrial biosynthesis preferentially impaired rapidly proliferating cells. Moreover, higher expression of this pathway was associated with greater mortality in breast cancer patients. Increased reliance on glycine may represent a metabolic vulnerability for selectively targeting rapid cancer cell proliferation.
Journal Article
Comparison of Global H i and Hα Line Profiles in MaNGA Galaxy Pairs with FAST
We present case studies comparing the global H i and Hα emission line profiles of six galaxy pairs. The six pairs are selected to have different nuclear activities, with two hosting an active galactic nucleus, and in different merging stages—two of each from the premerging, merging, and postmerging stages. We observe their global H i spectra with the Five-hundred-meter Aperture Spherical radio Telescope, achieving a noise level of ~0.5 mJy. Five out of the six pair systems have secure detections of H i emissions (signal-to-noise ratio > 10). The H i fraction and star formation efficiency of the six pairs do not deviate from isolated galaxies. For the H i line profiles, common unique asymmetry is observed, indicating disturbances of the atomic gas from the galaxy interaction. The global Hα spectra of the merger systems are constructed from the optical integral field spectroscopic observations by integrating the flux in corresponding line-of-sight velocity bins. The Hα spectra tend to show multiple components in the premerger phase and single-component line profiles in the postmerger systems, while all H i spectra show single-component line profiles regardless of merger stages. The H i and Hα spectra show offsets in the central velocities, which appear to decrease from >100 km s−1 in the premerger pair to <10 km s−1 in the postmergers. This trend is consistent with the scenario that, despite the significantly different distributions and kinematics of the atomic and ionized gases, the merging process may contribute to the mixing and eventually align various gas contents.
Journal Article
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Bis-indolyl benzenoids, hydroxypyrrolidine derivatives and other constituents from cultures of the marine sponge-associated fungus aspergillus candidus KUFA0062
Acknowledgments: This work was partially supported through national funds provided by the FCT/MCTES-Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE—Programa Operacional Factores de Competitividade (POFC) programme, under the project PTDC/MAR-BIO/4694/2014 (reference POCI-01-0145-FEDER-016790; Project 3599-Promover a Produção Científica e Desenvolvimento Tecnológico e a Constituição de Redes Temáticas (3599-PPCDT)) in the framework of the program PT2020 as well as by the project INNOVMAR-Innovation and Sustainability in the Management and Exploitation of Marine Resources (reference NORTE-01-0145-FEDER-000035, within Research Line NOVELMAR), supported by North Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). We thank Júlia Bessa and Sara Cravo for technical support.
Journal Article