Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and cancer. The zonal distribution of biomolecules in the liver is implicated in mediating the disease progression. Recently, G-protein-coupled receptor 35 (GPR35) has been highlighted to play a role in MASLD, but the precise mechanism is not fully understood, particularly, in a liver-zonal manner. Here, we aimed to identify spatially distributed specific genes and metabolites in different liver zonation that are regulated by GPR35 in MASLD, by combining lipid metabolomics, spatial transcriptomics (ST), and spatial metabolomics (SM). We found that GPR35 influenced lipid accumulation, inflammatory and metabolism-related factors in specific regions, notably affecting the anti-inflammation factor ELF4 (E74 like E-twenty six (ETS) transcription factor 4), lipid homeostasis key factor CIDEA (cell death-inducing DNA fragmentation factor alpha (DFFA)-like effector A), and the injury response-related genes SAA1/2/3 (serum amyloid A1/2/3), thereby impacting MASLD progression. Furthermore, SM elucidated specific metabolite distributions across different liver regions, such as C10H11N4O7P (3ʹ,5ʹ-cyclic inosine monophosphate (3ʹ,5ʹ-IMP)) for the central vein, and this metabolite significantly decreased in the liver zones of GPR35-deficient mice during MASLD progression. Taken together, GPR35 regulates hepatocyte damage repair, controls inflammation, and prevents MASLD progression by influencing phospholipid homeostasis and gene expression in a zonal manner.

Vitellogenins (VITs) are the most abundant proteins in adult hermaphrodite Caenorhabditis elegans. VITs are synthesized in the intestine, secreted to the pseudocoelom, matured into yolk proteins, and finally deposited in oocytes as nutrients for progeny development. How VITs are secreted out of the intestine remains unclear. Using immuno-electron microscopy (immuno-EM), we localize intestinal VITs along an exocytic pathway consisting of the rough endoplasmic reticulum (ER), the Golgi, and the lipid bilayer-bounded VIT vesicles (VVs). This suggests that the classic exocytotic pathway mediates the secretion of VITs from the intestine to the pseudocoelom. We also show that pseudocoelomic yolk patches (PYPs) are membrane-less and amorphous. The different VITs/yolk proteins are packed as a mixture into the above structures. The size of VVs can vary with the VIT levels and the age of the worm. On adult Day 2 (AD 2), intestinal VVs (~200 nm in diameter) are smaller than gonadal yolk organelles (YOs, ~500 nm in diameter). VVs, PYPs, and YOs share a uniform medium electron density by conventional EM. The morphological profiles documented in this study serve as a reference for future studies of VITs/yolk proteins.

Type 2 diabetes mellitus (T2DM) is closely associated with obesity, while interactions between the two diseases remain to be fully elucidated. To this point, we offer this perspective to introduce a set of new insights into the interpretation of T2DM spanning the etiology, pathogenesis, and treatment approaches. These include a definition of T2DM as an energy surplus-induced diabetes characterized by the gradual decline of β cell insulin secretion function, which ultimately aims to prevent the onset of severe obesity through mechanisms of weight loss. The body employs three adaptive strategies in response to energy surplus: the first one is adipose tissue expansion to store the energy for weight gain under normal weight conditions; the second one is insulin resistance to slow down adipose tissue expansion and weight gain under overweight conditions; and the third one is the onset of T2DM following β cell failure to reverse the weight gain in obese conditions. The primary signaling molecules driving the compensatory responses are adenosine derivatives, such as adenosine triphosphate (ATP), acetyl coenzyme A (acetyl-CoA), and reduced nicotinamide adenine dinucleotide (NADH). These molecules exert their effects through allosteric, post-translational, and transcriptional regulation of metabolic pathways. The insights suggest that insulin resistance and T2DM are protective mechanisms in the defense against excessive adiposity to avert severe obesity. The perspective provides a unified framework explaining the interactions between the two diseases and opens new avenues in the study of T2DM.