β3 adrenergic receptor (β3AR) agonists were originally developed to overcome obesity. Administration of selective β3AR agonist CL316,243 induces lipolysis and elevates the blood concentrations of growth differentiation factor 15 (GDF15), which exerts appetite-suppressing effects in mice. Liver is the main source of GDF15 in the circulation; however, it does not express β3AR. In this study, we hypothesized that free fatty acids (FFAs) released into the circulation upon lipolysis by the β3AR agonist induce GDF15 secretion from the liver. To verify this hypothesis, we manipulated the adiposity of mice using two different models, diet-induced obesity and surgical removal of white adipose tissue models, and measured the blood FFA and GDF15 levels after CL316,243 administration. Sustained elevation of blood FFA levels correlated with elevated blood GDF15 levels in the diet-induced obesity model. Conversely, surgical removal of white adipose tissue reduced the blood concentrations of FFAs and GDF15 after CL316,243 administration. Notably, CL316,243 failed to induce Gdf15 expression in AML12 mouse hepatocytes. However, FFAs induced Gdf15 expression in AML12 cells, with stearic acid acting as the most potent FFA. These data suggest that FFAs released via β3AR agonist-induced lipolysis increase Gdf15 expression levels in the liver and elevate blood GDF15 concentrations in mice. The sustained elevation of blood GDF15 levels in obese model mice by the β3AR agonist possibly reduced appetite more effectively in the obesity state than in the lean state.

Alcohol has a notable negative impact on global health. Understanding its physiological regulation is crucial to addressing alcohol use. Here, we show that FGF21-oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVHOXT)-dopamine neurons in the ventral tegmental area (VTADA) negatively regulate the drive to drink alcohol. Alcohol induces FGF21 signaling, which activates PVHOXT and induces oxytocin release in the VTA. The VTADA neurons are activated hours after alcohol ingestion, which reduces the drive to drink alcohol, extends the interdrink interval, and thereby reduces alcohol consumption. The system is downregulated in a mouse model of alcohol dependence, and activating the system with FGF21-inducing sugars reduces alcohol ingestion and prevents binge drinking and alcohol dependence. Therefore, FGF21-inducing nutraceuticals can substitute for alcohol by supplementing the FGF21-PVHOXT-VTADA negative feedback signal to attenuate alcohol-related behaviors in mice.

Alcoholic liver disease (ALD) is a significant health issue globally, arising as a consequence of excessive alcohol consumption. Currently, there is no specific pharmacotherapy for ALD, and the most effective treatment options remain abstinence or reduced alcohol intake. The Lieber-DeCarli liquid diet (LDC) has long been used to model ALD and other alcohol-related disorders in rodents. However, challenges in managing LDC, such as difficulties with food intake measurement and maintaining nutritional balance, complicate its use. To overcome these limitations, we developed a novel protocol by converting the liquid LDC into a solid form using agar, creating the solidified LDC diet (SLD). This adaptation facilitates precise control of food intake for pair-feeding and prevents nutritional deficiencies. Mice can be fed SLD either with or without 5% (w/w) ethanol over several weeks, and the addition of an oral ethanol gavage on the final day induces fatty liver and liver injury, mirroring the characteristics of ALD. This approach offers several advantages over traditional LDC, including streamlined diet preparation, consistent intake, and improved control over pair-feeding, reducing the variability of ethanol effects across subjects. The new SLD protocol promotes a more reliable modeling of ALD, contributing to more reproducible results and aiding research into pharmacological interventions for ALD and alcohol-related disorders.

Fibroblast growth factor (FGF) 21 activates oxytocin (OXT) neurons in the hypothalamus and suppresses simple sugar preference; however, alterations in the FGF21-OXT system in obesity remain unclear. In this study, we examined alterations in FGF21 secretion to systemic circulation and FGF21 sensitivity of OXT neurons in obesity, and the effects of FGF21-OXT dysfunction on feeding and body weight regulation. High-fat high-sucrose diet (HFHSD) feeding promoted hypersecretion of FGF21. The administration of recombinant FGF21 to normal diet-fed mice significantly activated OXT neurons in the paraventricular nucleus of the hypothalamus; this response was attenuated in HFHSD-fed mice. OXT neuron-specific FGF21 receptor-deficient (OXT-Klb cKO) mice were used as a model of FGF21-OXT dysfunction. The preference and appetite for sugar and fat were assessed using two-food choice test, two-bottle choice test, and lick microstructure analyses. The cKO mice showed an increased preference and appetite for FGF21-inducing simple sugars but not fat. These mice gained more weight when fed an HFHSD, which caused hyperphagia, but not when fed a high-fat diet. Therefore, obesity causes FGF21-OXT dysfunction, which promotes diet-induced obesity by increasing sugar appetite, suggesting that the dysfunction of the FGF21-OXT system plays a role in the vicious cycle of sugar-based diet-induced obesity in mice.NEW & NOTEWORTHY FGF21 activates OXT neurons and suppresses simple sugar preference, but the relationship between FGF21-OXT system and obesity is unknown. Here, we showed that obesity causes FGF21-OXT dysfunction and promotes sugar appetite and diet-induced obesity, suggesting that there is a vicious cycle of FGF21-OXT dysfunction and obesity in mice.

β3-Adrenoceptors (β3ARs) are expressed in the adipose tissue, the brain, and the bladder. In rodents, selective β3AR agonists have been shown to reduce normal chow intake through central and peripheral mechanisms. However, the impact of β3AR agonists on nutritional balance, as well as the relative contribution of each organ system to this effect, remains elusive. In this study, we aimed to determine whether the peripheral effect of β3AR agonists on food intake is nutrient-specific or energy in general using food choice experiments that allow for independent analysis of energy and nutrients. Mice were presented with two different diet options (normal diet [ND] vs. high-sucrose diet [HSD], high-fat diet [HFD], or high-protein diet [HPD]), and the effects of the β3AR agonist CL316,243 on the intake of these diets were examined. Treatment with CL316,243 reduced total energy intake, primarily through decreased consumption of HSD, HFD, and HPD. Accordingly, CL316,243 reduced food intake in a non-nutrient-specific manner, resulting in decreased caloric intake. In addition, CL316,243 increased plasma levels of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). In the ND vs. HSD food choice test, CL316,243 reduced HSD intake, even in liver-specific Fgf21 knockout mice. Furthermore, CL316,243 reduced food intake in mice with diet-induced obesity. These findings suggest that the CL316,243-mediated reduction in HSD intake occurs independently of liver-derived FGF21. Moreover, elevated plasma GDF15 levels were positively associated with reduced food intake induced by CL316,243.

Sugar intake induces the secretion of fibroblast growth factor 21 (FGF21) from the liver. Subsequently, FGF21 acts on the hypothalamus to reduce sugar intake. As simple sugars are obesogenic, low-calorie rare sugars can be used as alternatives. Accordingly, d-allulose, d-tagatose, and d-sorbitol induce Fgf21 expression in primary mouse hepatocytes. Carbohydrate-responsive element-binding protein regulates simple sugar-induced FGF21 expression. Therefore, this study aimed to determine whether the same mechanism was responsible for rare sugar-induced FGF21 expression. Promoter analysis, knockdown assays, and chromatin immunoprecipitation were performed using primary mouse hepatocytes. Our findings demonstrate that these three rare sugars transactivate the mouse Fgf21 promoter by inducing activating transcription factor 4 (ATF4), which binds to an amino acid response element located 1027 base pairs upstream of the transcription start site. These results suggested a novel mechanism for sugar-induced FGF21 expression.

Whether and how medium-chain triglyceride (MCT) intake is regulated remains unknown. Here, we showed that mice can discriminate between MCTs and LCTs. Hepatic β-oxidation participates in MCT-specific appetite, and hypothalamic galanin may be one of the factors that regulate MCT intake. Because of the antiobesity effects of MCTs, studying MCT-specific appetite may help combat obesity by promoting the intake of MCTs instead of LCTs.

Overconsumption of fat contributes to obesity and low adherence to dietary therapy in patients with obesity. The frequency of consuming soup dishes containing "dashi" (Japanese broth), a characteristic element of the Japanese diet, is negatively associated with obesity indicators. The use of dashi is considered one of the reasons why the low-fat Japanese diet is popular; however, whether and how dashi controls the selection and intake of fat is unknown. In this study, we tested the hypothesis that bonito broth, a typical Japanese dashi, affects fat consumption in a mouse model. First, we examined the long-term or short-term intake of corn oil emulsion in adult mice fed bonito broth. No significant effect was observed. Next, mouse dams were fed bonito broth during gestation or lactation and licking of 0.5, 1, 2.5, 5, and 10% corn oil in their adult pups was evaluated in acute tests. Compared to the control group, there were significant decreases in licks for some corn oil concentrations in the gestation and lactation groups. Finally, corn oil licking was tested in pups fed bonito broth after weaning. No significant effect was detected. This study suggests that dams’ intake of bonito broth during gestation or lactation reduces the intake of fat by their pups in adulthood.

De novo beige adipocyte biogenesis involves the proliferation of progenitor cells in white adipose tissue (WAT); however, what regulates this process remains unclear. Here, we report that in mouse models but also in human tissues, WAT lipolysis-derived linoleic acid triggers beige progenitor cell proliferation following cold acclimation, β3-adrenoceptor activation, and burn injury. A subset of adipocyte progenitors, as marked by cell surface markers PDGFRα or Sca1 and CD81, harbored cristae-rich mitochondria and actively imported linoleic acid via a fatty acid transporter CD36. Linoleic acid not only was oxidized as fuel in the mitochondria but also was utilized for the synthesis of arachidonic acid-derived signaling entities such as prostaglandin D2. Oral supplementation of linoleic acid was sufficient to stimulate beige progenitor cell proliferation, even under thermoneutral conditions, in a CD36-dependent manner. Together, this study provides mechanistic insights into how diverse pathophysiological stimuli, such as cold and burn injury, promote de novo beige fat biogenesis.

Background Sodium glucose co-transporter 2 (SGLT2) inhibitors are anti-diabetic drugs for type 2 diabetes that lower blood glucose levels and body weight. It is of special interest that SGLT2 inhibitors also improve liver metabolism and fatty liver. Liver is an important organ in regulation of energy metabolism, but the metabolic action of SGLT inhibitors in liver remains unclear.Methods We investigated the factors associated with the beneficial effects of dapagliflozin, a SGLT2 inhibitor, in the liver after confirming its glucose-lowering and weight loss effects using an obesity and diabetes mouse model. We also performed clinical study of patients with type 2 diabetes to explore candidate biomarkers that reflect the beneficial action of dapagliflozin in the liver.Findings In animal study, dapagliflozin induced autophagy in the liver (LC3-II to LC3-I expression ratio: P < 0.05 vs. control), and valine and leucine levels were increased in plasma (P < 0.01 vs. control) as well as in liver (P < 0.05 vs. control). Thus, increased plasma valine and leucine levels are potential biomarkers for improved liver metabolism. Clinical study found that valine and leucine levels were markedly higher in patients treated with dapagliflozin (valine: P < 0.05 vs. control, leucine: P < 0.01 vs. control) than those not treated after one week intervention.Interpretation Dapagliflozin improves liver metabolism via hepatic autophagy, and plasma valine and leucine levels may reflect its metabolic effect.Funding AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS), Japan Agency for Medical Research and Development (AMED), Novo Nordisk Pharma Ltd., and Japan Foundation for Applied Enzymology, and MSD Life Science Foundation International. Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Objective Although mental disorder is one of the most common comorbidities of rheumatoid arthritis (RA) and is known as a critical influence on RA remission rates, there is little knowledge regarding a possible therapeutic strategy for depression or anxiety in a RA population. Most recently, clinical evidence of dietary improvement for depression has emerged in a general population, but the relationship between dietary habits and mental disorder has not been investigated in RA. The purpose of this study is to elucidate clinical associations between mental disorder (depression/anxiety), dietary habits and disease activity/physical function in patients with RA. Methods A cross-sectional study was performed with 267 female outpatients from the KURAMA database. Using the Hospital Anxiety and Depression Scale (HADS), we classified the participants into three groups by depression state, and their characteristics were compared. Using the 20-items on the self-reported food frequency questionnaire, we investigated the relationship between dietary habits and depression or anxiety, adopting a trend test and a multivariate standardized linear regression analysis for the HADS score of depression or that of anxiety as a dependent variable. Results According to the classified stage of depression, current disease activity (DAS28-CRP: 28-Joint RA Disease Activity Score-C-reactive protein) and the health assessment questionnaire disability Index (HAQ-DI) were significantly increased. Trend analyses revealed that the depression score was inversely associated with the consumption of three food (fish, vegetables and fruit) out of twenty as was the anxiety score with only fish intake. Furthermore, multiple linear regression analysis revealed that the depression score was negatively associated with frequent fish intake (≥ 3 times per week) (Estimate -0.53, p = 0.033), HAQ-DI score within normal range (Estimate -0.88, p ≤ 0.001) and MTX use (Estimate -0.60, p ≤ 0.023). For the anxiety score, multivariate analysis showed similar but not significant associations with variables except for HAQ-DI score. Conclusions In a RA population, both depression and anxiety had a significant and negative association with HAQ-DI score, and depression rather than anxiety had negative association with frequent fish intake. Modification of dietary habits such as increased fish consumption may have a beneficial effect on the depression state in RA patients.

Obesity is a global epidemic leading to increased mortality and susceptibility to comorbidities, with few viable therapeutic interventions. A hallmark of disease progression is the ectopic deposition of lipids in the form of lipid droplets in vital organs such as the liver. However, the mechanisms underlying the dynamic storage and processing of lipids in peripheral organs remain an outstanding question. Here, we show an unexpected function for the major cap-binding protein, eIF4E, in high-fat-diet-induced obesity. In response to lipid overload, select networks of proteins involved in fat deposition are altered in eIF4E-deficient mice. Specifically, distinct messenger RNAs involved in lipid metabolic processing and storage pathways are enhanced at the translation level by eIF4E. Failure to translationally upregulate these mRNAs results in increased fatty acid oxidation, which enhances energy expenditure. We further show that inhibition of eIF4E phosphorylation genetically—and by a potent clinical compound—restrains weight gain following intake of a high-fat diet. Together, our study uncovers translational control of lipid processing as a driver of high-fat-diet-induced weight gain and provides a pharmacological target to treat obesity.

Background: Excessive salt intake is thought to exacerbate both development of hypertension and autoimmune diseases in animal models, but the clinical impact of excessive salt in rheumatoid arthritis (RA) patients is still unknown. We performed a cross-sectional study to clarify the associations between salt load index (urinary sodium-to-potassium ratio (Na/K ratio)), current disease activity and hypertension in an RA population.Methods: Three hundred thirty-six participants from our cohort database (KURAMA) were enrolled. We used the spot urine Na/K ratio as a simplified index of salt loading, and used the 28-Joint RA Disease Activity Score (DAS28-ESR) as an indicator of current RA disease activity. Using these indicators, we evaluated statistical associations between urinary Na/K ratio, DAS28-ESR and prevalence of hypertension.Results: Urinary Na/K ratio was positively associated with measured systolic and diastolic blood pressure and also with prevalence of hypertension even after covariate adjustment (OR 1.30, p < 0.001). In addition, increased urinary Na/K ratio was significantly and positively correlated with DAS28-ESR in multiple regression analysis (estimate 0.12, p < 0.001), as was also the case in gender-separated and prednisolone-separated sub-analyses.Conclusion: Urinary Na/K ratio was independently associated with current disease activity as well as with prevalence of hypertension in RA patients. Thus, dietary modifications such as salt restriction and potassium supplementation may well attenuate both disease activity and hypertension in RA patients.

While brown adipose tissue (BAT) is well-recognized for its ability to dissipate energy in the form of heat, recent studies suggest multifaced roles ofBATin the regulation of glucose and lipid homeostasis beyond stimulating thermogenesis. One of the functions involves interorgan communication with metabolic organs, such as the liver, throughBAT-derived secretory factors, a.k.a., batokine. However, the identity and the roles of such mediators remain insufficiently understood. Here, we employed proteomics and transcriptomics in human thermogenic adipocytes and identified previously unappreciated batokines, including phospholipid transfer protein (PLTP). We found that increased circulating levels ofPLTP, via systemic orBAT-specific overexpression, significantly improve glucose tolerance and insulin sensitivity, increased energy expenditure, and decrease the circulating levels of cholesterol, phospholipids, and sphingolipids. Such changes were accompanied by increased bile acids in the circulation, which in turn enhances glucose uptake and thermogenesis inBAT. Our data suggest thatPLTPis a batokine that contributes to the regulation of systemic glucose and lipid homeostasis as a mediator ofBAT-liver interorgan communication.

Cold stimuli and the subsequent activation of β-adrenergic receptor (β-AR) potently stimulate adipose tissue thermogenesis and increase whole-body energy expenditure. However, systemic activation of the β3-AR pathway inevitably increases blood pressure, a significant risk factor for cardiovascular disease, and, thus, limits its application for the treatment of obesity. To activate fat thermogenesis under tight spatiotemporal control without external stimuli, here, we report an implantable wireless optogenetic device that bypasses the β-AR pathway and triggers Ca 2+ cycling selectively in adipocytes. The wireless optogenetics stimulation in the subcutaneous adipose tissue potently activates Ca 2+ cycling fat thermogenesis and increases whole-body energy expenditure without cold stimuli. Significantly, the light-induced fat thermogenesis was sufficient to protect mice from diet-induced body-weight gain. The present study provides the first proof-of-concept that fat-specific cold mimetics via activating non-canonical thermogenesis protect against obesity.

It has been suggested that beige fat thermogenesis is tightly controlled by epigenetic regulators that sense environmental cues such as temperature. Here, we report that subcutaneous adipose expression of the DNA demethylase TET1 is suppressed by cold and other stimulators of beige adipocyte thermogenesis. TET1 acts as an autonomous repressor of key thermogenic genes, including Ucp1 and Ppargc1a, in beige adipocytes. Adipose-selective Tet1 knockout mice generated by using Fabp4-Cre improves cold tolerance and increases energy expenditure and protects against diet-induced obesity and insulin resistance. Moreover, the suppressive role of TET1 in the thermogenic gene regulation of beige adipocytes is largely DNA demethylase-independent. Rather, TET1 coordinates with HDAC1 to mediate the epigenetic changes to suppress thermogenic gene transcription. Taken together, TET1 is a potent beige-selective epigenetic breaker of the thermogenic gene program. Our findings may lead to a therapeutic strategy to increase energy expenditure in obesity and related metabolic disorders.

While brown adipose tissue (BAT) is well‐recognized for its ability to dissipate energy in the form of heat, recent studies suggest multifaced roles of BAT in the regulation of glucose and lipid homeostasis beyond stimulating thermogenesis. One of the functions involves interorgan communication with metabolic organs, such as the liver, through BAT‐derived secretory factors, a.k.a., batokine. However, the identity and the roles of such mediators remain insufficiently understood. Here, we employed proteomics and transcriptomics in human thermogenic adipocytes and identified previously unappreciated batokines, including phospholipid transfer protein (PLTP). We found that increased circulating levels of PLTP, via systemic or BAT‐specific overexpression, significantly improve glucose tolerance and insulin sensitivity, increased energy expenditure, and decrease the circulating levels of cholesterol, phospholipids, and sphingolipids. Such changes were accompanied by increased bile acids in the circulation, which in turn enhances glucose uptake and thermogenesis in BAT. Our data suggest that PLTP is a batokine that contributes to the regulation of systemic glucose and lipid homeostasis as a mediator of BAT‐liver interorgan communication. Phospholipid transfer protein (PLTP) released from BAT controls energy expenditure and systemic glucose/lipid homeostasis. The metabolic benefit of PLTP is mediated through a BAT‐liver interorgan communication that involves the regulation of lipoproteins and bile acids. Phospholipid transfer protein (PLTP) released from BAT controls energy expenditure and systemic glucose/lipid homeostasis. The metabolic benefit of PLTP is mediated through a BAT‐liver interorgan communication that involves the regulation of lipoproteins and bile acids.