Deficiency of Tristetraprolin Triggers Hyperthermia through Enhancing Hypothalamic Inflammation.

Tristetraprolin (TTP), an RNA-binding protein, controls the stability of RNA by capturing AU-rich elements on their target genes. It has recently been identified that TTP serves as an anti-inflammatory protein by guiding the unstable mRNAs of pro-inflammatory proteins in multiple cells. However, it has not yet been investigated whether TTP affects the inflammatory responses in the hypothalamus. Since hypothalamic inflammation is tightly coupled to the disturbance of energy homeostasis, we designed the current study to investigate whether TTP regulates hypothalamic inflammation and thereby affects energy metabolism by utilizing TTP-deficient mice. We observed that deficiency of TTP led to enhanced hypothalamic inflammation via stimulation of a variety of pro-inflammatory genes. In addition, microglial activation occurred in the hypothalamus, which was accompanied by an enhanced inflammatory response. In line with these molecular and cellular observations, we finally confirmed that deficiency of TTP results in elevated core body temperature and energy expenditure. Taken together, our findings unmask novel roles of hypothalamic TTP on energy metabolism, which is linked to inflammatory responses in hypothalamic microglial cells.

Enhanced lipid utilization is coupled to the sickness responses triggered by lipopolysaccharide.

Sickness symptoms exerted via inflammatory responses occur in several infectious and chronic diseases. A growing body of evidence suggests that altered nutrient availability and metabolism are tightly coupled to inflammatory processes. However, the relationship between metabolic shifts and the development of the sickness response has not been explored fully. Therefore, we aimed to evaluate metabolic phenotypes with a mouse model showing sickness symptoms via systemic administration of lipopolysaccharide (LPS) in the present study. LPS injection elevated the lipid utilization and circulating levels of fatty acids. It also increased the levels of ß-hydroxybutyric acid, a ketone body produced from fatty acids. We confirmed the functional connectivity between nutrient utilization and inflammatory responses and demonstrated enhanced lipid utilization in the hypothalamus providing insights into hypothalamic control of sickness responses. Collectively, these findings could help develop new therapeutic strategies to treat patients with severe sickness symptoms associated with infectious and chronic human diseases.

The Acute Effects of Swimming Exercise on PGC-1α-FNDC5/Irisin-UCP1 Expression in Male C57BL/6J Mice.

Irisin is a myokine primarily secreted by skeletal muscles and is known as an exercise-induced hormone. The purpose of this study was to determine whether the PGC-1α -FNDC5 /Irisin-UCP1 expression which is an irisin-related signaling pathway, is activated by an acute swimming exercise. Fourteen to sixteen weeks old male C57BL/6J mice (n = 20) were divided into control (CON, n = 10) and swimming exercise groups (SEG, n = 10). The SEG mice performed 90 min of acute swimming exercise, while control (non-exercised) mice were exposed to shallow water (2 cm of depth) for 90 min. The mRNA and protein expression of PGC-1α, FNDC5 and browning markers including UCP1 were evaluated by quantitative real-time PCR and western blotting. Serum irisin concentration was measured by enzyme-linked immunosorbent assay. An acute swimming exercise did not lead to alterations in the mRNA and protein expression of PGC-1α in both soleus and gastrocnemius muscles, the mRNA and protein expression of UCP1 in brown adipose tissue, mRNA browning markers in visceral adipose tissue and circulating irisin when compared with the control group. On the other hand, an acute swimming exercise led to increases in the mRNA and protein expressions of FNDC5 in the soleus muscle, the protein expression of FNDC5 in the gastrocnemius muscles and the protein expression of UCP1 in subcutaneous adipose tissue.

Adiponectin Controls Nutrient Availability in Hypothalamic Astrocytes.

Adiponectin, an adipose tissue-derived hormone, plays integral roles in lipid and glucose metabolism in peripheral tissues, such as the skeletal muscle, adipose tissue, and liver. Moreover, it has also been shown to have an impact on metabolic processes in the central nervous system. Astrocytes comprise the most abundant cell type in the central nervous system and actively participate in metabolic processes between blood vessels and neurons. However, the ability of adiponectin to control nutrient metabolism in astrocytes has not yet been fully elucidated. In this study, we investigated the effects of adiponectin on multiple metabolic processes in hypothalamic astrocytes. Adiponectin enhanced glucose uptake, glycolytic processes and fatty acid oxidation in cultured primary hypothalamic astrocytes. In line with these findings, we also found that adiponectin treatment effectively enhanced synthesis and release of monocarboxylates. Overall, these data suggested that adiponectin triggers catabolic processes in astrocytes, thereby enhancing nutrient availability in the hypothalamus.

Obesity induced by estrogen deficiency is associated with hypothalamic inflammation.

Occurrence of obesity during the postmenopausal period is closely associated with inflammatory processes in multiple peripheral organs that are metabolically active. Hypothalamic inflammation has been recognized as one of the major underlying causes of various metabolic disorders, including obesity. The association between menopause-related obesity and hypothalamic inflammation remains poorly understood. We observed an elevation in hypothalamic inflammation in the ovariectomized mice, which displayed altered metabolic phenotypes and visceral obesity. Furthermore, we confirmed that ovariectomized mice displayed microglial activation accompanied by the upregulation of multiple genes involved in the inflammatory responses in hypothalamic microglia. Collectively, the current findings suggest that hypothalamic inflammation associated with microglial functioning could be a major pathogenic element in disruption of energy homeostasis during the postmenopausal period.

Beta-Aminoisobutyric Acid Inhibits Hypothalamic Inflammation by Reversing Microglia Activation.

Beta-aminoisobutyric acid (BAIBA), a natural thymine catabolite, is involved in the beneficial effects of exercise on metabolic disorders. In particular, it has been reported to reverse the inflammatory processes observed in the peripheral organs of animal models of obesity. Therefore, this study aimed to investigate whether BAIBA improves hypothalamic inflammation, which is also tightly coupled with the development of obesity. We observed that treatment with BAIBA effectively reversed palmitic acid-induced hypothalamic inflammation and microglial activation in vivo. Consistent with these findings, we confirmed that BAIBA reversed body weight gain and increased adiposity observed in mice fed with a high-fat diet. Collectively, the current findings evidence the beneficial impacts of BAIBA on the imbalance of energy metabolism linked to hypothalamic inflammation.