Publications in Cell Metabolism

The immune system defends against pathogens but can also cause tissue damage, energetic costs, and even death through excessive cytokine and chemokine production. Because antimicrobial responses are necessary for host defense, hosts have evolved cooperative defenses to mitigate the costs of immunity. Using Yersinia pseudotuberculosis infection in mice, we demonstrate that dietary methionine supplementation protects against cytokine-mediated anorexia, wasting, blood-brain barrier dysfunction, and lethality without impairing microbial killing. Methionine and its metabolite S-adenosyl methionine (SAM) activate renal mTORC1 signaling, promoting renal growth and enhanced glomerular filtration function. This enables urinary clearance of pro-inflammatory cytokines from the circulation, limiting their systemic accumulation and the resulting sickness and lethality. This work reveals an unappreciated role for the kidneys in controlling systemic cytokine responses during infection. It also suggests that nutrient-based interventions targeting metabolic signaling can mitigate the harmful trade-offs of immune defense, offering potential therapeutic avenues to reduce infection-related costs, including death.

Inexorable increases in insulin resistance, lipolysis, and hepatic glucose production (HGP) are hallmarks of type 2 diabetes. Previously, we showed that peripheral delivery of exogenous fibroblast growth factor 1 (FGF1) has robust anti-diabetic effects mediated by the adipose FGF receptor (FGFR) 1. However, its mechanism of action is not known. Here, we report that FGF1 acutely lowers HGP by suppressing adipose lipolysis. On a molecular level, FGF1 inhibits the cAMP-protein kinase A axis by activating phosphodiesterase 4D (PDE4D), which separates it mechanistically from the inhibitory actions of insulin via PDE3B. We identify Ser44 as an FGF1-induced regulatory phosphorylation site in PDE4D that is modulated by the feed-fast cycle. These findings establish the FGF1/PDE4 pathway as an alternate regulator of the adipose-HGP axis and identify FGF1 as an unrecognized regulator of fatty acid homeostasis.

Oh et al. identify diagnostic signatures for fibrosis from stool metagenomic and metabolomic profiling that, when combined with serum AST levels, distinguishes cirrhosis in mixed fibrosis cohort. Moreover, this combination signature was validated in racially and geographically independent cohorts.

Most neurons are not replaced during an animal’s lifetime. This nondividing state is characterized by extreme longevity and age-dependent decline of key regulatory proteins. To study the lifespans of cells and proteins in adult tissues, we combined isotope labeling of mice with a hybrid imaging method (MIMS-EM). Using 15N mapping, we show that liver and pancreas are composed of cells with vastly different ages, many as old as the animal. Strikingly, we also found that a subset of fibroblasts and endothelial cells, both known for their replicative potential, are characterized by the absence of cell division during adulthood. In addition, we show that the primary cilia of beta cells and neurons contains different structural regions with vastly different lifespans. Based on these results, we propose that age mosaicism across multiple scales is a fundamental principle of adult tissue, cell, and protein complex organization. Arrojo e Drigo et al. measure the age of cells and proteins using high-resolution isotope imaging and show that adult mouse organs are mosaics of cells of different ages. The liver, which has high turnover, contains cells as old as the animal, while cilia have differentially aged structural protein components.