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Partial substitution of chemical fertilizers by organic amendments is essential for improving the soil quality without yield loss. Fungi play an important role in soil quality because they decompose organic matter and cycle nutrients in the soil. However, there is limited information regarding the effect of different organic substitution rates (OSRs) on the soil quality and fungal community. This study investigated the relationship between the soil quality index and fungal community in a tea plantation under different OSRs of N, from a single application of synthetic fertilizer (NPK) to 100% N substitution with organic fertilizer (OM100). The OSRs were positively correlated with the soil physicochemical and biological soil quality index (SQI), but only the physicochemical SQI exhibited a significant relationship with tea production. The OSR also shifted the soil fungal community composition. Soil pH, soil organic C (SOC), microbial biomass C (MBC), and available potassium (AK) were the key characteristics that were significantly correlated with the variation of soil fungal community. Network analysis indicated that additional organic substitution can enhance the soil fungal network complexity, which also showed a positive correlation with the SQI. These results confirmed the feasibility of organic substitution for soil quality improvement, and implied that the soil fungal network complexity could be a new indicator for soil quality assessment.

Fibroblast growth factor 21 (FGF21) has been identified as a potent metabolic regulator. Administration of recombinant FGF21 protein to rodents and rhesus monkeys with diet-induced or genetic obesity and diabetes exerts strong antihyperglycemic and triglyceride-lowering effects and reduction of body weight. Despite the importance of FGF21 in the regulation of glucose, lipid, and energy homeostasis, the mechanisms by which FGF21 functions as a metabolic regulator remain largely unknown. Here we demonstrate that FGF21 regulates energy homeostasis in adipocytes through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), resulting in enhanced mitochondrial oxidative function. AMPK phosphorylation levels were increased by FGF21 treatment in adipocytes as well as in white adipose tissue from ob/ob mice. FGF21 treatment increased cellular NAD⁺ levels, leading to activation of SIRT1 and deacetylation of its downstream targets, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and histone 3. Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1α activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an AMPK-SIRT1-PGC1α-dependent mechanism in adipocytes.

Soil respiration (Rs) plays an important role in the carbon (C) dynamics of terrestrial ecosystems and is strongly regulated by nitrogen (N) inputs. While the impact of N fertilization on Rs has been widely documented in conventional farmland ecosystems, its patterns and influencing factors in perennial tea plantation systems are still poorly understood. In the study, we conducted a 15-year field experiment in a representative tea plantation to investigate the effects of different N rates (0, 112.5, 225, and 450 kg N ha−1 yr−1) on Rs. Compared to the control (N0), soil pH decreased significantly (p < 0.05) by 6.07%, 11.82%, and 16.12% under N112.5, N225, and N450, respectively. Concurrently, cation exchange capacity (CEC), ammonium (NH4+-N), nitrate (NO3−-N), and available phosphorus (AP) increased with increasing N rates, whereas available potassium (AK) decreased. Soil microbial biomass carbon (MBC) initially increased and then decreased with increasing N rates, while dissolved organic carbon (DOC) content increased consistently. The Rs rate exhibited a distinct seasonal pattern with a single peak in August. The annual mean Rs rates were 2.79, 3.15, 4.06, and 3.85 μmol·m−2·s−1 for the N0, N112.5, N225, and N450 treatments, respectively. Soil temperature explained 55.41% to 61.08% of the variation in Rs rates across N treatments, and a composite model incorporating both soil temperature and moisture further improved the prediction of Rs dynamics. Cumulative soil CO2 emissions (CCEs) over the study period ranged from 10,427 to 14,221 kg CO2-C ha−1 across treatments and were significantly negatively correlated with soil pH, and positively correlated with DOC, MBC, and NO3−-N content. A non-linear relationship between N application rate and CCEs was observed, highlighting the complexity of optimizing N management for balancing productivity and climate mitigation in tea plantation systems. These findings provide a theoretical basis for developing rational N fertilization strategies and improving the predictive capacity of C cycle models in agroecosystems.

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia. Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.

Muscle wasting is one of the main characteristics of cachexia associated with cancer and other chronic diseases and is often exacerbated by antineoplastic agents. Increased oxidative stress is associated with muscle wasting, along with depletion of glutathione, the most abundant endogenous antioxidant. Therefore, boosting endogenous glutathione has been proposed as a therapeutic strategy to prevent muscle wasting. Here, we tested this hypothesis by inactivating CHAC1, an intracellular glutathione degradation enzyme. We found CHAC1 expression is increased under multiple muscle wasting conditions in animal models, including fasting, cancer cachexia, and chemotherapy. The elevation of muscle Chac1 expression is associated with reduced glutathione level. CHAC1 inhibition via CRSPR/Cas9 mediated knock-in of an enzyme inactivating mutation demonstrates a novel strategy to preserve muscle glutathione levels under wasting conditions but fails to prevent muscle wasting in mice. These results suggest that preserving intracellular glutathione level alone may not be sufficient to prevent cancer or chemotherapy induced muscle wasting.

GDF15 is a distant TGF-β family member that induces anorexia and weight loss. Due to its function, GDF15 has attracted attention as a potential therapeutic for the treatment of obesity and its associated metabolic diseases. However, the pharmacokinetic and physicochemical properties of GDF15 present several challenges for its development as a therapeutic, including a short half-life, high aggregation propensity, and protease susceptibility in serum. Here, we report the design, characterization and optimization of GDF15 in an Fc-fusion protein format with improved therapeutic properties. Using a structure-based engineering approach, we combined knob-into-hole Fc technology and N-linked glycosylation site mutagenesis for half-life extension, improved solubility and protease resistance. In addition, we identified a set of mutations at the receptor binding site of GDF15 that show increased GFRAL binding affinity and led to significant half-life extension. We also identified a single point mutation that increases p-ERK signaling activity and results in improved weight loss efficacy in vivo. Taken together, our findings allowed us to develop GDF15 in a new therapeutic format that demonstrates better efficacy and potential for improved manufacturability.

The responses of nitrous oxide (N2O) emissions to nitrogen (N) application in acidic, perennial agricultural systems, and the factors driving these emissions, remain poorly understood. To address this gap, a 12-year field experiment was conducted to investigate the effects of different N application rates (0, 112.5, 225, and 450 kg N ha−1 yr−1) on N2O emissions, tea yield, and the associated driving factors in a tea plantation. The study found that soil pH significantly decreased with long-term N application, dropping by 0.32 to 0.85 units. Annual tea yield increased significantly, by 148–243%. N application also elevated N2O emission fluxes by 33–277%, with notable seasonal fluctuations observed. N2O flux was positively correlated with N rates, water-filled pore space (WFPS), soil temperature (Tsoil), and inorganic N (NH4+-N and NO3−-N), while showing a negative correlation with soil pH. Random forest (RF) modeling identified WFPS, N rates, and Tsoil as the most important variables influencing N2O flux. The cumulative N2O emissions for N112.5, N225, and N450 were 1584, 2791, and 45,046 g N ha−2, respectively, representing increases of 1.33, 2.34, and 3.77 times compared to N0. The N2O-N emission factors (EF) were 0.35%, 0.71%, and 0.74%, respectively, and increased with higher N rates. These findings highlight the importance of selecting appropriate fertilization timing and improving water and fertilizer management as key strategies for mitigating soil acidification, enhancing nitrogen use efficiency (NUE), and reducing N2O emissions in acidic tea-plantation systems. This study offers a theoretical foundation for developing rational N fertilizer management practices and strategies aimed at reducing N2O emissions in tea-plantation soils.

From a forward mutagenetic screen to discover mutations associated with obesity, we identified mutations in the Spag7 gene linked to metabolic dysfunction in mice. Here, we show that SPAG7 KO mice are born smaller and develop obesity and glucose intolerance in adulthood. This obesity does not stem from hyperphagia, but a decrease in energy expenditure. The KO animals also display reduced exercise tolerance and muscle function due to impaired mitochondrial function. Furthermore, SPAG7-deficiency in developing embryos leads to intrauterine growth restriction, brought on by placental insufficiency, likely due to abnormal development of the placental junctional zone. This insufficiency leads to loss of SPAG7-deficient fetuses in utero and reduced birth weights of those that survive. We hypothesize that a ‘thrifty phenotype’ is ingrained in SPAG7 KO animals during development that leads to adult obesity. Collectively, these results indicate that SPAG7 is essential for embryonic development and energy homeostasis later in life. Obesity rates are climbing worldwide, leading to an increase in associated conditions such as type 2 diabetes. While new pharmaceutical approaches are available to help individuals manage their weight, many patients do not respond to them or experience prohibitive side effects. Identifying alternative treatments will likely require pinpointing the genes and molecular actors involved in the biological processes that control weight regulation. Previous research suggests that a protein known as SPAG7 could help shape how mice use and store the energy they extract from food. Flaherty et al. therefore set out to investigate the role this protein plays in the body. To do so, they created a line of mice born without SPAG7, which they monitored closely throughout life. These animals were underweight at birth and did not eat more than other mice, yet they were obese as adults. Their ability to exercise was reduced, their muscles were weaker and contained fibers with functional defects. The mice also exhibited biological changes associated with the onset of diabetes. Yet deleting SPAG7 during adulthood led to no such changes; these mice maintained normal muscle function and body weight. Closely examining how SPAG7-deficient mice developed in the womb revealed placental defects which likely caused these animals to receive fewer nutrients from their mother. Such early-life deprivation is known to be associated with the body shifting towards maximizing its use of resources and privileging fat storage, even into and throughout adulthood. By shedding light on the biological role of SPAG7, the work by Flaherty et al. helps to better understand how developmental events can increase the likelihood of obesity later in life. Further investigations are now needed to explore whether this knowledge could help design interventions relevant to human health.

Cachexia is a wasting syndrome involving adipose, muscle, and body weight loss in cancer patients. Tumor loss-of-function mutations in STK11 / LKB1 , a regulator of AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are linked to weight loss in non-small cell lung cancer (NSCLC) patients. This study examines the role of the integrated stress response (ISR) cytokine growth differentiation factor 15 (GDF15) in regulating cachexia using patient-derived and engineered STK11/LKB1 -mutant NSCLC lines. Tumor cell-derived serum GDF15 levels are elevated in mice bearing these tumors. Treatment with a GDF15-neutralizing antibody or silencing GDF15 from tumor cells prevents adipose/muscle loss, strength decline, and weight reduction, identifying tumors cells as the GDF15 source. Restoring wild-type STK11/LKB1 in NSCLC lines with endogenous STK11/LKB1 loss reverses the ISR and reduces GDF15 expression rescuing the cachexia phenotype. Collectively, these findings implicate tumor-derived GDF15 as a key mediator and therapeutic target in STK11/LKB1 -mutant NSCLC-associated cachexia. GDF15 has been associated with cancer-associated cachexia. Here, the authors show that STK11/LKB1 loss-of-function mutations in non-small cell lung cancer result in an exaggerated integrated stress response culminating in the tumor cell secretion of the cytokine GDF15 promoting cachexia.

As a main agronomic intervention in tea cultivation, nitrogen (N) application is useful to improve tea yield and quality. However, the effects of N application on the formation of tea quality-related metabolites have not been fully studied, especially in long-term field trials. In this study, a 10-year field experiment was conducted to investigate the effect of long-term N application treatments on tea quality-related metabolites, their precursors, and related gene expression. Long-term N application up-regulated the expression of key genes for chlorophyll synthesis and promoted its synthesis, thus increasing tea yield. It also significantly increased the contents of total free amino acids, especially l-theanine, in fresh tea leaves, while decreasing the catechin content, which is conducive to enhancing tea liquor freshness. However, long-term N application significantly reduced the contents of benzyl alcohol and 2-phenylethanol in fresh tea leaves, and also reduced (E)-nerolidol and indole in withered leaves, which were not conducive to the formation of floral and fruity aroma compounds. In general, an appropriate amount of N fertilizer (225 kg/hm2) balanced tea yield and quality. These results not only provide essential information on how N application affects tea quality, but also provide detailed experimental data for field fertilization.