Brown adipose tissue (BAT) plays a critical role in diet-induced thermogenesis, a process by which excess energy intake is consumed as heat. Several studies have suggested that hepatocytes regulate diet-induced thermogenesis in response to changes in nutritional status. However, the precise mechanisms by which hepatocytes contribute to this process are not yet fully understood.
Sex differences in metabolism and cardiometabolic disease risk are well described. Because estrogen action is thought to underlie female-biased protection of immunometabolism and cardiometabolic health, we selectively deleted the estrogen receptor alpha (ERa, encoded by Esr1) from myeloid cells of mice to understand the impact of estrogen action on macrophage function. Our previous findings in other glucoregulatory cell types point to an important role of ERa in the control of mitochondrial form and function. Mitochondria play a critical role in innate immunity, and disruption of mitochondrial function is linked to the pathogenesis of cardiometabolic disease. In addition to a primary role in energy production, mitochondria are central in the regulation of iron homeostasis, a critical process governing immune cell function. Myeloid-specific Esr1 knockout mice (MACER) showed increased diet-induced glucose intolerance, insulin resistance, adiposity, and atherosclerotic lesion area compared with f/f controls. A key phenotype of MACER mice was marked accumulation of iron in liver, spleen, gonadal white adipose tissue, and bone marrow-derived macrophages compared with f/f controls. Specifically, iron accumulated in mitochondria from macrophages within tissues of MACER mice. Iron accumulation was linked with alteration of mitochondrial inner and outer membrane morphology and mtDNA replication machinery, and associated with increased transferrin receptor (Tfrc) expression and cellular inflammation driven by interleukin-1-β. We utilized chromatin immunoprecipitation approaches to identify novel ERa-regulated chromatin structures and target genes that modulate immunometabolism of macrophages. Our findings indicate that Esr1 is critical in the regulation of mitochondrial metabolism and iron homeostasis in macrophages, and the action of ERa is critical for the protection against inflammation and cardiometabolic-related disease. Disclosure H.Iwasaki: None. B.K.Leyva: None. A.Ma: None. N.L.Yang: None. P.H.Tran: None. Z.Zhou: None. A.L.Hevener: None. Funding National Institutes of Health (DK128957)
Brown adipose tissue (BAT) is a major organ responsible for diet-induced thermogenesis, a phenomenon which converts excess energy intake into heat. Previous studies suggested that hepatocytes regulate diet-induced thermogenesis in response to changes in nutritional status. However, it is not clear how hepatocytes are involved in diet-induced thermogenesis.
Background: Mitochondria play an essential role in the heat generation in beige adipocytes. Their number and function are regulated in response to external stimuli such as cold exposure and beta-3 adrenergic receptor (β3-AR) agonist. Previously, we have reported that miR-494 regulates mitochondrial biogenesis in the skeletal muscle. However, this remains unknown in beige adipocytes. Aim: We investigated the role of miR-494 on mitochondrial biogenesis during adipogenesis and browning. Result: C57BL/6J mice were subjected to intermittent mild cold exposure. The expression levels of peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC1-α) and mitochondrial proteins including mitochondrial transcription factor A (TFAM), pyruvate dehydrogenase (PDH), mitochondrially encoded cytochrome c oxidase (MTCO1) and uncoupling protein 1 (Ucp1) were strongly increased in inguinal white adipose tissue (iWAT). On the contrary, that of miR-494 resulted in 27% reduction (p < 0.05) in iWAT following 12°C cold exposure for 6 hours. Furthermore, β3-AR stimulation potently reduced miR-494 expression in 3T3-L1 beige cells. Overexpression of miR-494 substantially reduced the protein expression of PGC1-α and its downstream targets such asTFAM and MTCO1 (p < 0.05). In contrast, antisense of miR-494 significantly increased the expression of TFAM, MTCO1 and PDH (p < 0.05). Overexpression of miR-494 strongly decreased the oxygen consumption rate in 3T3-L1 beige cells and protein expression of PGC1-α and Ucp1 (p < 0.05) in primary beige adipocytes. Finally, we explored the direct target of miR-494 and found that 3`UTR region of PGC1-α is a direct target of miR-494 by luciferase assay. Conclusion: These findings demonstrate that miR-494 directly inhibits the expression of PGC1-α in adipose tissue. The decreased miR-494 expression during adipocyte differentiation removes its inhibitory effect, leading to stimulation of Ucp1 expression and mitochondrial biogenesis. Disclosure M. Lemecha: None. K. Morino: Research Support; Self; Astellas Pharma US, Inc., AstraZeneca, Sunstar Inc., CMIC Pharmascience, Kowa Pharmaceutical. T. Imamura: None. H. Iwasaki: None. N. Ohashi: None. H. Yamamoto: None. S. Ugi: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., MSD K.K. H. Maegawa: Speaker's Bureau; Self; Astellas Pharma US, Inc.. Research Support; Self; Astellas Pharma US, Inc.. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Nippon Boehringer Ingelheim Co. Ltd.. Research Support; Self; Nippon Boehringer Ingelheim Co. Ltd.. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Daiichi Sankyo Company, Limited, Takeda Pharmaceutical Company. Speaker's Bureau; Self; Takeda Pharmaceutical Company, Novo Nordisk A/S, Eli Lilly and Company.
Adaptive thermogenesis is enhanced not only by cold exposure but also by feeding, which is considered as a partial defense mechanism against obesity. We have previously demonstrated that whole-body knockout mice of a metallopeptidase nardilysin (NRDC) show hypothermia and cold intolerance. Despite these phenotypes, NRDC-deficient mice (NRDC-KO) show enhanced adaptive thermogenesis in brown adipose tissue (BAT), which is due to the increased heat dissipation. Here we found that NRDC expression in the liver is increased by fasting and decreased by re-feeding in wild-type mice. To elucidate the liver-specific role of NRDC in energy metabolism, we established hepatocyte-specific NRDC deficient mice (LKO). Unexpectedly, LKO showed an enhanced BAT thermogenesis and whole-body energy expenditure, indicating the role of NRDC in inter-organ network of liver and BAT. Notably, the phenotypic difference between control and LKO was eliminated by hepatic vagotomy or the elevation of ambient temperature to thermoneutrality (30℃), suggesting that hepatic NRDC regulates BAT thermogenesis via the nervous control of heat dissipation. Indeed, LKO showed a significant increase in skin blood flow of the plantar at room temperature (23℃). Together, diet controls NRDC expression in liver, which in turn regulates adaptive thermogenesis in BAT through the control of skin blood flow.
Abstract Objective This study investigated the effects of tadalafil on the urethra and detrusor in the initial phase of diabetes in rats. Methods Thirty‐six female Sprague‐Dawley rats were assigned to a non‐diabetes (ND), diabetes (D), or tadalafil‐treated diabetes (DT) group (n = 12 per group), with the DT group receiving oral tadalafil (2 mg/kg/d) for 7 days before the experiments. Seven weeks after diabetes induction (by a single intraperitoneal injection of streptozotocin), urethral and intravesical pressure were simultaneously recorded in vivo, whereas responses of detrusor strips to potassium chloride (30 mM), electrical field stimulation (EFS) and carbachol were measured in vitro. Results The intravesical pressure at which the urethra started to relax was significantly lower in the DT than D group (mean [± s.d.] 18.9 ± 2.9 vs 29.1 ± 6.6 cm H 2 O; P < .05). In addition, the reduction in urethral pressure was significantly larger in the DT than D group (−10.9 ± 4.0 vs −4.0 ± 2.9 cm H 2 O; P < .05). Detrusor stimulation revealed that the mean contractile responses to EFS and carbachol were significantly lower in the ND and DT groups than in the D group (120.7 ± 26.5% and 130.8 ± 15.8% vs 200.1 ± 47.9% of the 30 mM KCl‐induced contraction, respectively, in response to 50 Hz EFS [ P < .05]; 211.1 ± 35.4% and 208.4 ± 25.3% vs 425.7 ± 125.0% of the 30 mM KCl‐induced contraction, respectively, in response to 10 −3 M carbachol [ P < .05]). Conclusions Tadalafil restored urethral relaxation function and detrusor responses to EFS and carbachol during the initial phase of diabetes.
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