bims-mimead 2026-10-18 papers

Int J Obes (Lond). 2026 Oct 16.

Adipose tissue transcriptome before and after surgery: effects on genes driving lipid metabolism, inflammation, and RNA processing.

Prince Dadson, Maria K Jaakkola, Lihua Sun, Riku Klén, Tomi Suomi, Maija Vaittinen, Ioanna A Anastasiou, Henri Honka, Heidi Immonen, Robert M Badeau, Paulina Salminen, Mika Helmiö, Anne Roivainen, Laura Pekkarinen, Kari K Kalliokoski, Eleni Rebelos, Vesa M Olkkonen, Pirjo Nuutila.

AIMS: Obesity, marked by excess adipose tissue, is strongly associated with increased cardiometabolic risk. Metabolic bariatric surgery (MBS) leads to significant and sustained weight loss and improves metabolic profiles in persons with severe obesity. However, how MBS induces persistent transcriptional changes in adipose tissue and their contributions to cardiometabolic improvements remain unclear. This study examined subcutaneous (SAT) and visceral (VAT) adipose tissue transcriptome profiles in people with severe obesity, tracking changes in SAT after MBS, with a focus on lipid metabolism, inflammation, RNA processing, and cholesterol handling.
METHODS: This study included 42 women with severe obesity undergoing MBS and 15 sex-matched healthy people without obesity as controls. Targeted RNA expression profiling was performed on SAT and VAT samples.
RESULTS: In people with obesity, SAT showed higher expression of genes related to adipocyte function, anti-inflammatory markers, extracellular matrix remodeling, lipid metabolism, cell-death regulation, oxidative stress protection, mRNA processing, and cholesterol handling compared to VAT. In contrast, VAT showed elevated expression of genes linked to inflammation, complement activation, stress signaling, cell death, lipid biosynthesis, and mRNA processing. Compared with controls, SAT in obesity showed increased inflammatory and stress-response gene expression and upregulation of RNA processing regulators, but reduced de novo lipogenesis and cholesterol synthesis. Following MBS, SAT showed restored expression of lipogenic and adipogenic genes alongside downregulation of inflammatory, cholesterol biosynthesis, and splicing-factor genes.
CONCLUSIONS: These findings demonstrate SAT and VAT remodeling in obesity and show that MBS partially reverses transcriptional changes in SAT, providing mechanistic insight into its metabolic benefits. They also highlight the need for targeted therapeutic strategies to more fully restore adipose tissue function and improve long-term metabolic outcomes.
CLINICALTRIALS:
GOV REGISTRATION NUMBERS: NCT00793143 and NCT01373892.

DOI: https://doi.org/10.1038/s41366-026-02243-8

Nature. 2026 Oct 14.

Artificial intelligence-enabled clinical phenotyping of human brown fat.

Nicolás Gómez-Banoy, Jorge A Barrero, Luiza Rachel Pinheiro de Carvalho, Caroline S Jiang, Tara Doma Lama, Nakul Karandikar, Mascha Koenen, Tiffany Lam, Kaja Plucińska, Ksenia Morozova, Stephanie Chahwan, Gustavo Barraza, Burcin Agridag Ucpinar, Jennifer E Liu, Rohit Sharma, Daniel Lafontaine, Heiko Schöder, Paul Cohen.

Adipose tissue has a central role in systemic energy balance and the pathogenesis of obesity and its sequelae1,2. In contrast to white adipose tissue, brown adipose tissue (BAT) uses energy to produce heat3. Detectable BAT in humans is associated with decreased prevalence of cardiometabolic diseases4. However, the complete spectrum of health conditions associated with BAT remains unknown, and high-throughput methods to quantify BAT activity in humans are lacking5,6. Here we leveraged big data and artificial intelligence to systematically define the clinical impact of BAT in a cohort of 101,243 patients from a large cancer centre. Our unbiased analyses revealed that, across all diagnoses, cardiovascular and psychiatric diseases were less prevalent in people with BAT. Using a machine learning approach, we semi-automatically quantified BAT activity in approximately 8,700 patients and demonstrated that higher BAT activity, especially in the axillary depot, is associated with lower odds of cardiometabolic diseases and healthier white fat distribution. People with BAT also exhibited more favourable glycaemic parameters, lipid profiles, inflammatory markers and echocardiographic indices. Analysis of medication usage demonstrated that angiotensin receptor blocker use was positively associated with BAT presence. As proof of concept, we showed that the angiotensin receptor blocker losartan increased brown adipocyte activity and whole-body energy expenditure. Altogether, our studies harnessing artificial intelligence and big data identify new clinical phenotypes linked to BAT and serve as a platform for drug repurposing to activate this tissue in humans.

DOI: https://doi.org/10.1038/s41586-026-11162-7

J Clin Invest. 2026 Oct 08. pii: e200951. [Epub ahead of print]

Manganese availability determines hepatic insulin sensitivity by enhancing Akt activity.

Jennifer R Gamarra, Sei Higuchi, Timothy L Yuan, Yuke Xie, Cong Liu, Niroshan Shanmugarajah, Hang Yang, Meredith O Kelly, Sarah A Hannou, Kathrin Schilling, Ana Navas-Acien, Eunhee Choi, Anum Glasgow, Inna I Astapova, Mark A Herman, Rebecca A Haeusler.

Insulin signaling is a critical determinant of metabolic health, and impairments in insulin action contribute to the development of type 2 diabetes. The kinase Akt is a central mediator of insulin signaling and is required for insulin's suppression of hepatic glucose output. Although the regulation of Akt by the insulin receptor-PI3K pathway is well understood, there are instances in which signaling downstream of Akt is dissociated from proximal insulin signaling, for example in insulin resistance. Nonetheless, little is known about PI3K-independent mechanisms of Akt regulation. Here, we discovered that hepatocyte manganese concentrations are a key determinant of PI3K-independent Akt function in vivo. We further demonstrated that manganese increases Akt's catalytic efficiency, and quantitative phosphoproteomics revealed that manganese and insulin act additively to enhance Akt activity. Moreover, we uncovered that hepatic manganese concentrations fluctuate during fasting and feeding via carbohydrate-dependent transcriptional regulation of the manganese efflux transporter Slc30a10. This dynamic metal-signaling axis provides a mechanistic link between nutrient status and Akt activation, and suggests a molecular explanation for the glucose-lowering effects of manganese observed in humans. Our findings establish manganese as a physiologically regulated cofactor for Akt and position metal bioavailability as a previously unrecognized layer of insulin signaling control.

Keywords: Cell biology; Glucose metabolism; Insulin; Metabolism; Protein kinases

DOI: https://doi.org/10.1172/JCI200951

iScience. 2026 Oct 16. 29(10): 117672

Divergent ectopic fat distribution and adipokine/hepatokine levels characterize the metabolically healthy overweight/obesity phenotype.

Antonio Clavero-Jimeno, Juan J Martin-Olmedo, Alessandro Gatti, Adrián Cortés-Martín, Alba Camacho-Cardenosa, Lucas Jurado-Fasoli, Manuel Dote-Montero, Marcos Molina-Fernandez, Alejandro López-Vázquez, Amaya Lopez-Pascual, Matías A Ávila, Estrella Petrina, Ana Zugasti, Iñigo Urdiain, Mara Concepción, Rafael Cabeza, José L Martín-Rodríguez, Idoia Labayen, Jonatan R Ruiz.

The metabolically healthy overweight/obesity (MHOO) phenotype combines excess adiposity with preserved cardiometabolic health. We compared specific fat depots, circulating adipokine and hepatokine levels, and fecal microbiota composition between 384 adults classified as MHOO (n = 99) or metabolically unhealthy overweight/obesity (MUOO; n = 285). Magnetic resonance imaging was used to quantify visceral adipose tissue (VAT) volume, hepatic and pancreatic fat fractions, abdominal and mid-thigh intermuscular adipose tissue (IMAT), and subcutaneous adipose tissue (SAT). Despite similar whole-body fat mass, MHOO showed lower VAT volume, hepatic and pancreatic fat fractions, abdominal IMAT volume, abdominal VAT-to-SAT ratio, and mid-thigh IMAT area, together with higher mid-thigh SAT area. MHOO also had higher adiponectin and sex hormone-binding globulin (SHBG) and lower retinol-binding protein 4 (RBP4) levels. Fecal microbiota composition was similar between groups. VAT volume and hepatic fat fraction were the strongest discriminative features, supporting fat distribution rather than total adiposity as a key feature of preserved metabolic health.

Keywords: cytokines; ectopic fat; gut microbiome; hepatic steatosis; obesity phenotypes; pancreatic steatosis

DOI: https://doi.org/10.1016/j.isci.2026.117672