Mucosal TLR5 activation controls healthspan and longevity.

Addressing age-related immunological defects through therapeutic interventions is essential for healthy aging, as the immune system plays a crucial role in controlling infections, malignancies, and in supporting tissue homeostasis and repair. In our study, we show that stimulating toll-like receptor 5 (TLR5) via mucosal delivery of a flagellin-containing fusion protein effectively extends the lifespan and enhances the healthspan of mice of both sexes. This enhancement in healthspan is evidenced by diminished hair loss and ocular lens opacity, increased bone mineral density, improved stem cell activity, delayed thymic involution, heightened cognitive capacity, and the prevention of pulmonary lung fibrosis. Additionally, this fusion protein boosts intestinal mucosal integrity by augmenting the surface expression of TLR5 in a certain subset of dendritic cells and increasing interleukin-22 (IL-22) secretion. In this work, we present observations that underscore the benefits of TLR5-dependent stimulation in the mucosal compartment, suggesting a viable strategy for enhancing longevity and healthspan.

Effects of high fat diet-induced obesity on pathophysiology, immune cells, and therapeutic efficacy in systemic lupus erythematosus.

Prior studies have suggested a strong link between obesity and autoimmune diseases. This study aimed to evaluate the effects of high fat diet (HFD)-induced obesity on the disease pathogenesis, immune cell infiltration, and therapeutic efficacy in systemic lupus erythematosus (SLE). Treatment with methylprednisolone significantly increased the survival in the control diet group, but not in the HFD group. An HFD significantly increased the incidence of severe proteinuria and glucose intolerance. Regardless of the diet, treatment with methylprednisolone significantly decreased the serum levels of anti-dsDNA antibodies, IL-2, IL-10, and interferon γ-induced protein 10 (IP-10), and improved the renal pathology scores. Treatment with methylprednisolone significantly lowered the serum levels of IL-6, MCP-1, and TNF-α in the control diet group, but not in the HFD group. HFD significantly increased the proportions of CD45+ and M1 cells and significantly decreased the proportion of M2 cells in white adipose tissue; methylprednisolone treatment significantly rescued this effect. In the HFD group, methylprednisolone treatment significantly decreased the M1:M2 and increased the Foxp3+:RORγt+ cell in the spleen compared with the untreated group. These data improve our understanding of the effect of HFD on the therapeutic efficacy of corticosteroids in SLE treatment, which could have clinical implications.

Erratum to: Exercise-induced beige adipogenesis of iWAT in Cidea reporter mice.

[Erratum to: BMB Reports 2022; 55(4): 187-191, PMID: 35000670, PMCID: PMC9058471] The BMB Reports would like to correct in BMB Rep. 55(4):187-191, titled "Exercise-induced beige adipogenesis of iWAT in Cidea reporter mice". This research was supported by the Research Institute for Veterinary Science, Seoul National University. Since grant name and number are incorrect, this information has now been corrected as follows: This research was supported by Korea Mouse Phenotyping Project (2013M3A9D5072550) of the National Research Foundation (NRF) funded by the Ministry of Science and ICT and partially supported by the Brain Korea 21 Plus Program and the Research Institute for Veterinary Science of Seoul National University. The authors apologize for any inconvenience or confusion that may be caused by this error. The ACKNOWLEDGEMENTS of Original PDF version have been corrected.

Aerobic exercise for eight weeks provides protective effects towards liver and cardiometabolic health and adipose tissue remodeling under metabolic stress for one week: A study in mice.

BACKGROUND: The relationship between exercise training and health benefits is under thorough investigation. However, the effects of exercise training on the maintenance of metabolic health are unclear. METHODS: Our experimental design involved initial exercise training followed by a high-fat diet (HFD) challenge. Eight-week-old male was trained under voluntary wheel running aerobic exercise for eight weeks to determine the systemic metabolic changes induced by exercise training and whether such changes persisted even after discontinuing exercise. The mice were given either a normal chow diet (NCD) or HFD ad libitum for one week after discontinuation of exercise (CON-NCD, n = 29; EX-NCD, n = 29; CON-HFD, n = 30; EX-HFD, n = 31). RESULTS: Our study revealed that metabolic stress following the transition to an HFD in mice that discontinued training failed to reverse the aerobic exercise training-induced improvement in metabolism. We report that the mice subjected to exercise training could better counteract weight gain, adipose tissue hypertrophy, insulin resistance, fatty liver, and mitochondrial dysfunction in response to an HFD compared with untrained mice. This observation could be attributed to the fact that exercise enhances the browning of white fat, whole-body oxygen uptake, and heat generation. Furthermore, we suggest that the effects of exercise persist due to PPARα-FGF21-FGFR1 mechanisms, although additional pathways cannot be excluded and require further research. Although our study suggests the preventive potential of exercise, appropriate human trials are needed to demonstrate the efficacy in subjects who cannot perform sustained exercise; this may provide an important basis regarding human health.

Exercise-induced beige adipogenesis of iWAT in Cidea reporter mice.

Obesity is caused by an imbalance between energy intake and energy expenditure. Exercise is attracting attention as one of the ways to treat obesity. Exercise induces 'beige adipogenesis' in white adipose tissue, increasing total energy expenditure via energy dissipation in the form of heat. Also, beige adipogenesis can be induced by treatment with a beta-adrenergic receptor agonist. We developed a Cidea-dual reporter mouse (Cidea-P2ALuc2-T2A-tdTomato, Luciferase/tdTomato) model to trace and measure beige adipogenesis in vivo. As a result, both exercise and injection of beta-adrenergic receptor agonist induced beige adipogenesis and was detected through fluorescence and luminescence. We confirmed that exercise and beta-adrenergic receptor agonist induce beige adipogenesis in Cidea-dual reporter mouse, which will be widely used for detecting beige adipogenesis in vivo. [BMB Reports 2022; 55(4): 187-191].

Targeting PLD2 in adipocytes augments adaptive thermogenesis by improving mitochondrial quality and quantity in mice.

Phospholipase D (PLD)2 via its enzymatic activity regulates cell proliferation and migration and thus is implicated in cancer. However, the role of PLD2 in obesity and type 2 diabetes has not previously been investigated. Here, we show that during diet-induced thermogenesis and obesity, levels of PLD2 but not PLD1 in adipose tissue are inversely related with uncoupling protein 1, a key thermogenic protein. We demonstrate that the thermogenic program in adipose tissue is significantly augmented in mice with adipocyte-specific Pld2 deletion or treated with a PLD2-specific inhibitor and that these mice are resistant to high fat diet-induced obesity, glucose intolerance, and insulin resistance. Mechanistically, we show that Pld2 deletion in adipose tissue or PLD2 pharmacoinhibition acts via p62 to improve mitochondrial quality and quantity in adipocytes. Thus, PLD2 inhibition is an attractive therapeutic approach for obesity and type 2 diabetes by resolving defects in diet-induced thermogenesis.

Neural regulation of energy and bone homeostasis by the synaptic adhesion molecule Calsyntenin-3.

Neuronal regulation of energy and bone metabolism is important for body homeostasis. Many studies have emphasized the importance of synaptic adhesion molecules in the formation of synapses, but their roles in physiology still await further characterization. Here, we found that the synaptic adhesion molecule Calsyntenin-3 (CLSTN3) regulates energy and bone homeostasis. Clstn3 global knockout mice show reduced body mass with improved leptin sensitivity and increased energy expenditure compared to their wild-type littermates. In addition, Clstn3 knockout mice show reduced marrow volume and cortical bone mass without alteration of trabecular bone microarchitecture. This reduced bone mass is not bone cell-autonomous because neither osteoblast- nor osteoclast-specific Clstn3 knockout mice show bone defects; similarly, in vitro cultures of both Clstn3 knockout osteoblasts and osteoclasts do not show any defects. These reduced body and bone mass phenotypes can be attributed instead to neuronal CLSTN3 because they are recapitulated by pan-neuronal but not sympathetic neuron-specific deletion of Clstn3. This study reveals novel physiological functions of neuronal Clstn3 as a key regulator of energy and bone homeostasis.