bims-stacyt 2023-11-19 papers

J Endocrinol Invest. 2023 Nov 13.

Gastric GDF15 levels are regulated by age, sex, and nutritional status in rodents and humans.

V Pena-Leon, R Perez-Lois, M Villalon, C Folgueira, S Barja-Fernández, E Prida, J Baltar, F Santos, J Fernø, T García-Caballero, R Nogueiras, M Quiñones, O Al-Massadi, L M Seoane.

AIM: Growth differentiation factor 15 (GDF15) is a stress response cytokine that has been proposed as a relevant metabolic hormone. Descriptive studies have shown that plasma GDF15 levels are regulated by short term changes in nutritional status, such as fasting, or in obesity. However, few data exist regarding how GDF15 levels are regulated in peripheral tissues. The aim of the present work was to study the variations on gastric levels of GDF15 and its precursor under different physiological conditions, such as short-term changes in nutritional status or overfeeding achieved by HFD. Moreover, we also address the sex- and age-dependent alterations in GDF15 physiology.
METHODS: The levels of gastric and plasma GDF15 and its precursor were measured in lean and obese mice, rats and humans by western blot, RT-PCR, ELISA, immunohistochemistry and by an in vitro organ culture system.
RESULTS: Our results show a robust regulation of gastric GDF15 production by fasting in rodents. In obesity an increase in GDF15 secretion from the stomach is reflected with an increase in circulating levels of GDF15 in rats and humans. Moreover, gastric GDF15 levels increase with age in both rats and humans. Finally, gastric GDF15 levels display sexual dimorphism, which could explain the difference in circulating GFD15 levels between males and females, observed in both humans and rodents.
CONCLUSIONS: Our results provide clear evidence that gastric GDF15 is a critical contributor of circulating GDF15 levels and can explain some of the metabolic effects induced by GDF15.

Keywords: Age; GDF15; Obesity; Sex; Stomach

DOI: https://doi.org/10.1007/s40618-023-02232-y

bioRxiv. 2023 Nov 04. pii: 2023.11.02.565321. [Epub ahead of print]

Lac-Phe mediates the anti-obesity effect of metformin.

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformin's effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levels in vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformin's anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformin's effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

DOI: https://doi.org/10.1101/2023.11.02.565321

PLoS Biol. 2023 Nov;21(11): e3002367

Carbon dioxide regulates cholesterol levels through SREBP2.

Nityanand Bolshette, Saar Ezagouri, Vaishnavi Dandavate, Iuliia Karavaeva, Marina Golik, Hu Wang, Peter J Espenshade, Timothy F Osborne, Xianlin Han, Gad Asher.

In mammals, O2 and CO2 levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O2 sensing are well characterized, little is known regarding the signaling pathways that participate in CO2 signaling and adaptation. Here, we show that CO2 levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO2 regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO2 triggers SREBP2 activation through changes in endoplasmic reticulum (ER) membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO2 signaling and that cellular cholesterol levels can be modulated by CO2 through SREBP2.

DOI: https://doi.org/10.1371/journal.pbio.3002367