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Publication Impact of Fish Oil Intake and Hyperthermia Therapy on Metabolic Health(2024-09) Fan, RongAging is a major contributor to decreased metabolic rate, underscoring the need to develop effective strategies to combat this decline. Interventions that combine lifestyle adjustments with dietary strategies could be particularly effective in reducing the risks of metabolic dysfunction. Hyperthermia/heat treatment (HT) is a therapeutic practice that has been demonstrated to provide a variety of metabolic benefits. Fish oil (FO) is a potent dietary intervention that promotes metabolic health. However, whether HT could promote metabolic health by combating aging-associated metabolic slowdown and the combinational effect of FO and HT have not yet been evaluated. The first aim was to investigate the impact of HT on aging-associated metabolic dysfunction and to determine the underlying molecular mechanisms, including potential associations with gut microbiota. Next, we also aimed to unravel the synergistic effect of HT and FO supplementation on aging-related obesity and metabolic dysfunction in both aged female mice and ovariectomized (OVX) mice. Our overarching hypothesis was that HT and FO synergistically improve metabolic health by promoting energy expenditure and improving insulin sensitivity and inflammation response in aging and menopause. Our findings indicate that daily HT at 40-41℃ for 30 min showed no tissue damage and significantly reduced lactate dehydrogenase (LDH) levels in older females, indicating a decline in aging-mediated tissue damage. HT effectively countered weight gain induced by a high-fat diet in both aged female and ovariectomized mice. Furthermore, HT demonstrated significant improvements in 1) insulin sensitivity and insulin signaling in inguinal white adipose tissue (iWAT), 2) reduced lipid accumulation in the liver and brown fat, and 3) increased fatty acid beta-oxidation in the liver and iWAT. An increase in the expression of transient receptor potential vanilloid 1 (TRPV1) and genes associated with Ca2+/ATP-pump on the plasma membrane and endoplasmic reticulum (ER) suggests that HT triggers ATP-consuming futile calcium cycling. These findings were confirmed in human brown adipocytes. HT alone notably lowered core body temperature (~0.5℃) across all diets, leading to a reduced Firmicutes to Bacteroidetes ratio and significant changes in gut microbiome diversity and composition. Additionally, microbiota genera Tuzzerella, Defluviitaleaceae_UCG-011, Alistipes, and Enterorhabdus were significantly correlated with liver, brown adipose tissue weights, and core body temperature. The combination of HT and FO showed a more substantial improvement in metabolic health and insulin sensitivity. Additionally, FO supplementation significantly increased the abundance of [Eubacterium]_coprostanoligenes_group, a genus known for reducing cholesterol absorption and associated with lower plasma lipids and body weight. HT and FO intake correlated with a decrease in Alistipes, which are usually present with obesity and inflammation conditions. In the OVX mice, Colidextribacter and Muribaculaceae showed increased abundance in the HT group compared to the CON group. FO combined with HT increased the abundance of the microbial genera [Eubacterium]_coprostanoligenes_group, Bacteroides, and Incertae_Sedis, which negatively correlated with core body temperature. HT, FO, or the combination of HT and FO, did not have a similar effect in OVX mice compared to the aged female mice, suggesting a potential effect of the absence of estrogen on the microbiota. Overall, the findings of this dissertation demonstrate that HT and FO supplementation, independently and in combination, significantly enhance metabolic health by improving insulin sensitivity, promoting thermogenic energy expenditure, and modulating gut microbiota diversity and composition. The combinational effects of HT and FO are more potent in aged female mice compared to the OVX mouse model of menopause.