This review focuses on mechanisms of calorie restriction (CR), particularly the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis as an evolutionary conserved signal that regulates aging and lifespan, underlying the effects of CR in mammals. Topics include (1) the relation of the GH-IGF-1 signal with chronic low-level inflammation as one of the possible causative factors of aging, that is, inflammaging, (2) the isoform specificity of the forkhead box protein O (FoxO) transcription factors in CR-mediated regulation of cancer and lifespan, (3) the role for FoxO1 in the tumor-inhibiting effect of CR, (4) pleiotropic roles for FoxO1 in the regulation of disorders, and (5) sirtuin (Sirt) as a molecule upstream of FoxO. From the evolutionary view, the necessity of neuropeptide Y (Npy) for the effects of CR and the pleiotropic roles for Npy in life stages are also emphasized. Genes for mediating the effects of CR and regulating aging are context-dependent, particularly depending on nutritional states.

Obesity is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), which is initiated by adipocyte-macrophage crosstalk. Among the possible molecules regulating this crosstalk, we focused on neuropeptide Y (NPY), which is known to be involved in hypothalamic appetite and adipose tissue inflammation and metabolism. In this study, the NPY^−/− mice showed a marked decrease in body weight and adiposity, and lower free fatty acid and adipose inflammation without food intake alteration during a high fat diet (HFD). Moreover, NPY deficiency increased the thermogenic genes expression in brown adipose tissue. Notably, NPY-mRNA expression was upregulated in macrophages from the HFD mice compared to that from the mice on a standard diet. The NPY-mRNA expression also positively correlated with the liver mass/body weight ratio. NPY deletion alleviated HFD-induced adipose inflammation and liver steatosis. Hence, our findings point toward a novel intracellular mechanism of NPY in the regulation of adipocyte-macrophage crosstalk and highlight NPY antagonism as a promising target for therapeutic approaches against obesity and NAFLD.

Background & Objectives: The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is intrinsically linked to nutrient overload and obesity, and adipose dysfunction. While continuous dietary stress triggers adipose-tissue-derived lipotoxicity and disrupts hepatic metabolic homeostasis and provokes inflammation, the transcriptional scaffolds that mitigate this lipotoxicity remain incompletely understood. We investigated the role of zinc finger protein 90 (ZFP90) in defending against diet-induced metabolic stress and MASLD pathogenesis. Methods: Wild-type and ZFP90-knockout mice were subjected to a high-fat diet (HFD) to model nutrient-overload-induced MASLD. Hepatic phenotypes were characterized using metabolic profiling and RNA sequencing. Mechanistic dynamics were evaluated through protein interaction assays, and clinical relevance was validated using human MASLD liver biopsies. Results: ZFP90 deficiency significantly accelerated HFD-induced steatosis, systemic insulin resistance, and inflammatory infiltration. Crucially, ZFP90 depletion drove severe white adipose tissue (WAT) dysfunction, characterized by impaired lipogenic capacity, exacerbated lipolysis, and diminished local insulin signaling. This was accompanied by a pro-inflammatory secretory shift in WAT, evident from decreased Adipoq and increased Cd68/Ccl3 expression. In the liver, transcriptomic analysis revealed a profound induction of pathways related to fatty acid uptake and cytokine signaling. Mechanistically, ZFP90 forms a repressive complex with TRIM28, acting as a crucial molecular brake on NF-κB signaling. Loss of ZFP90 unleashes p65-mediated hyper-inflammation. Clinically, hepatic ZFP90 expression is significantly upregulated in patients with MASLD. Conclusions: ZFP90 is a novel regulator of immunometabolic homeostasis under dietary stress. By forming of complex with Trim28 to inhibit the nuclear translocation of NF-κB, ZFP90 suppresses pro-inflammatory responses and protects the liver from obesity-associated systemic lipotoxicity. These finding provide critical insights into the adipo-hepatic axis and highlight the ZFP90 as a promising therapeutic target to mitigate the progression to metabolic dysfunction-associated steatohepatitis (MASH).

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become increasingly common, a trend driven by obesity, excess nutritional intake, and dysfunctional adipose tissue. While continuous dietary stress triggers adipose-tissue-derived lipotoxicity and disrupts hepatic metabolic homeostasis and provokes inflammation, the transcriptional scaffolds that mitigate this lipotoxicity remain incompletely understood. We investigated the role of zinc finger protein 90 (ZFP90) in defending against diet-induced metabolic stress and MASLD pathogenesis. Methods: Wild-type and ZFP90-knockout mice were subjected to a high-fat diet (HFD) to model nutrient-overload-induced MASLD. Hepatic phenotypes were characterized using metabolic profiling and RNA sequencing. Mechanistic dynamics were evaluated through protein interaction assays, and clinical relevance was validated using human MASLD liver biopsies. Results: ZFP90 deficiency significantly accelerated HFD-induced steatosis, systemic insulin resistance, and inflammatory infiltration. Crucially, ZFP90 depletion drove severe white adipose tissue (WAT) dysfunction, characterized by impaired lipogenic capacity, exacerbated lipolysis, and diminished local insulin signaling. This was accompanied by a pro-inflammatory secretory shift in WAT, evident from decreased Adipoq and increased Cd68/Ccl3 expression. In the liver, transcriptomic analysis revealed a profound induction of pathways related to fatty acid uptake and cytokine signaling. Mechanistically, ZFP90 forms a repressive complex with TRIM28, acting as a crucial molecular brake on NF-kB signaling. Loss of ZFP90 unleashes p65-mediated hyper-inflammation. Clinically, hepatic ZFP90 expression is significantly upregulated in patients with MASLD. Conclusions: ZFP90 is a novel regulator of immunometabolic homeostasis under dietary stress. By forming of complex with Trim28 to inhibit the nuclear translocation of NF-κB, ZFP90 suppresses pro-inflammatory responses and protects the liver from obesity-associated systemic lipotoxicity. These findings provide critical insights into the adipo-hepatic axis and highlight ZFP90 as a promising therapeutic target to mitigate the progression to metabolic dysfunction-associated steatohepatitis (MASH).