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Tag: thermogenesis (Page 1 of 2)

Lack of p38 activation in T cells increases IL-35 and protects against obesity by promoting thermogenesis

Ivana Nikolić, Irene Ruiz-Garrido, María Crespo, Rafael Romero-Becerra, Luis Leiva-Vega, Alfonso Mora, Marta León, Elena Rodríguez, Magdalena Leiva, Ana Belén Plata-Gómez, Maria Beatriz Alvarez Flores, Jorge L Torres, Lourdes Hernández-Cosido, Juan Antonio López, Jesús Vázquez, Alejo Efeyan, Pilar Martin, Miguel Marcos & Guadalupe Sabio.

Obesity is characterized by low-grade inflammation, energy imbalance and impaired thermogenesis. The role of regulatory T cells (Treg) in inflammation-mediated maladaptive thermogenesis is not well established.

Reduction of fat mass of mice lacking MKK3/6 as seen by MRI (Image: Ivana Nikolić).

Here, we find that the p38 pathway is a key regulator of T cell-mediated adipose tissue (AT) inflammation and browning. Mice with T cells specifically lacking the p38 activators MKK3/6 are protected against diet-induced obesity, leading to an improved metabolic profile, increased browning, and enhanced thermogenesis. We identify IL-35 as a driver of adipocyte thermogenic program through the ATF2/UCP1/FGF21 pathway. IL-35 limits CD8+ T cell infiltration and inflammation in AT. Interestingly, we find that IL-35 levels are reduced in visceral fat from obese patients.

Mechanistically, we demonstrate that p38 controls the expression of IL-35 in human and mouse Treg cells through mTOR pathway activation. Our findings highlight p38 signaling as a molecular orchestrator of AT T cell accumulation and function.

A combination of a dopamine receptor 2 agonist and a kappa opioid receptor antagonist synergistically reduces weight in diet-induced obese rodents

Beatriz Cicuéndez, Javier Pérez-García & Cintia Folgueira.

As the global obesity rate increases, so does the urgency to find effective anti-obesity drugs. In the search for therapeutic targets, central nervous system (CNS) mechanisms engaged in the regulation of energy expenditure and food intake, such as the opioid and dopamine systems, are crucial.

Increased temperature in a mouse treated with BC and PF-04455242 (Image: Cintia Folgueira).

In this study, we examined the effect on body weight of two drugs: bromocriptine (BC), a D2R receptor agonist, and PF-04455242, a selective κ opioid receptor (KOR) antagonist. Using diet-induced obese (DIO) rats, we aimed to ascertain whether the administration of BC and PF-04455242, independently or in combination, could enhance body weight loss. Furthermore, the present work demonstrates that the peripheral coadministration of BC and PF-04455242 enhances the reduction of weight in DIO rats and leads to a decrease in adiposity in a food-intake-independent manner. These effects were based on heightened energy expenditure, particularly through the activation of brown adipose tissue (BAT) thermogenesis.

Overall, our findings indicate that the combination of BC and PF-04455242 effectively induces body weight loss through increased energy expenditure by increasing thermogenic activity and highlight the importance of the combined use of drugs to combat obesity.

DIDO is necessary for the adipogenesis that promotes diet-induced obesity

María Ángeles García-López, Alfonso Mora, Patricia Corrales, Tirso Pons, Ainhoa Sánchez de Diego, Amaia Talavera Gutiérrez, Karel H. M. van Wely, Gema Medina-Gómez, Guadalupe Sabio, Carlos Martínez-A, & Thierry Fischer.

The prevalence of overweight and obesity continues to rise in the population worldwide. Because it is an important predisposing factor for cancer, cardiovascular diseases, diabetes mellitus, and COVID-19, obesity reduces life expectancy. Adipose tissue (AT), the main fat storage organ with endocrine capacity, plays fundamental roles in systemic metabolism and obesity-related diseases. Dysfunctional AT can induce excess or reduced body fat (lipodystrophy). Dido1 is a marker gene for stemness; gene-targeting experiments compromised several functions ranging from cell division to embryonic stem cell differentiation, both in vivo and in vitro.

Reduced  body temperature in mutant ΔNT mice.
Reduced body temperature in mutant ΔNT mice (Image: Alfonso Mora).

We report that mutant mice lacking the DIDO N terminus show a lean phenotype. This consists of reduced AT and hypolipidemia, even when mice are fed a high-nutrient diet. DIDO mutation caused hypothermia due to lipoatrophy of white adipose tissue (WAT) and dermal fat thinning. Deep sequencing of the epididymal white fat (Epi WAT) transcriptome supported Dido1 control of the cellular lipid metabolic process. We found that, by controlling the expression of transcription factors such as C/EBPα or PPARγ, Dido1 is necessary for adipocyte differentiation, and that restoring their expression reestablished adipogenesis capacity in Dido1 mutants.

Our model differs from other lipodystrophic mice and could constitute a new system for the development of therapeutic intervention in obesity.

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