Kinin B1 receptor controls maternal adiponectin levels and influences offspring weight gain.

Given the importance of the kinin B1 receptor in insulin and leptin hormonal regulation, which in turn is crucial in maternal adaptations to ensure nutrient supply to the fetus, we investigated the role of this receptor in maternal metabolism and fetoplacental development. Wild-type and kinin B1 receptor-deficient (B1KO) female mice were mated with male mice of the opposite genotype. Consequently, the entire litter was heterozygous for kinin B1 receptor, ensuring that there would be no influence of offspring genotype on the maternal phenotype. Maternal kinin B1 receptor blockade reduces adiponectin secretion by adipose tissue ex vivo, consistent with lower adiponectin levels in pregnant B1KO mice. Furthermore, fasting insulinemia also increased, which was associated with placental insulin resistance, reduced placental glycogen accumulation, and heavier offspring. Therefore, we propose the combination of chronic hyperinsulinemia and reduced adiponectin secretion in B1KO female mice create a maternal obesogenic environment that results in heavier pups.

Metabolic fasting stress is ameliorated in Kinin B1 receptor-deficient mice.

The liver has an essential role in responding to metabolic demands under stress conditions. The organ stores, releases, and recycles metabolism-related substrates. However, it is not clear how the Kallikrein-Kinin System modulates metabolic flexibility shift between energetic sources. AIMS: To analyze the hepatic metabolism in kinin B1 receptor deficient mice (B1KO mice) under fasting conditions. MAIN METHODS: WT and B1KO male mice were allocated in a calorimetric cage for 7 days and 48 h before the euthanasia, half of the animals of both groups were under fasting conditions. Biochemical parameters, ketone bodies (KB), and gene expression involving the liver energetic metabolism genes were evaluated. KEY FINDINGS: Kinin B1 receptor (B1R) modulates the metabolic shift under fasting conditions, reducing the VO2 expenditure. A preference for carbohydrates as an energetic source is suggested, as the B1KO group did not display an increase in KB in the serum. Moreover, the B1KO animals displayed higher serum triglycerides concentration compared to WT fasting mice. Interestingly, the lack of B1R induces the increase expression of enzymes from the glycolysis and lipolysis pathways under the fed. However, under fasting, the enzymatic expression of gluconeogenesis, glyceroneogenesis, and ketogenesis of these pathways does not occur, suggesting an absence of the shift metabolism responsivity, and this condition is modulated by PDK4 under FOXO1 control. SIGNIFICANCE: B1R has an important role in the hepatic glucose metabolism, which in turn influences the energetic metabolism, and in long-term outcomes, such as in the decrease in hepatic glycogen stores and in the enhancement of hepatic metabolism.

Cortisol Dose-Dependently Impairs Migration and Tube-like Formation in a Trophoblast Cell Line and Modulates Inflammatory and Angiogenic Genes.

Several stimuli can change maternal hormone levels during pregnancy. These changes may affect trophoblastic cells and modulate the development of the embryo and the placental tissue itself. Changes in cortisol levels are associated with impaired trophoblast implantation and function, in addition to other pregnancy complications. This study aims to analyze the effects of low and high doses of cortisol on an extravillous trophoblast cell line, and the effects of various exposures to this hormone. SGHPL-4 cells were treated with cortisol at five doses (0-1000 nM) and two exposures (continuous: 24 h/day; and intermittent: 2 h/day). In intermittent treatment, cortisol acted mainly as an anti-inflammatory hormone, repressing gene expression of kinin B1 receptors, interleukin-6, and interleukin-1ß. Continuous treatment modulated inflammatory and angiogenic pathways, significantly repressing angiogenic factors and their receptors. Cortisol affected cell migration and tube-like structures formation. In conclusion, both continuous and intermittent exposure to cortisol repressed the expression of inflammatory genes, while only continuous exposure repressed the expression of angiogenic genes, suggesting that a sustained increase in the levels of this hormone is more harmful than a high short-term increase. Cortisol also impaired tube-like structures formation, and kinin receptors may be involved in this response.

Interleukin-6 deficiency modulates testicular function by increasing the expression of suppressor of cytokine signaling 3 (SOCS3) in mice.

Several cytokines have been reported to participate in spermatogenesis, including interleukin-6 (IL6). However, not many studies have been conducted on the loss of Il6 on the male reproductive tract. Nonetheless, there is considerable knowledge regarding the pathological and physiological role of IL6 on spermatogenesis. In this way, this study evaluated the impact of Il6 deficiency on mice testicles in the absence of infection or inflammation. We showed that Il6 deficiency increases daily sperm production, the number of spermatids, and the testicular testosterone and dihydrotestosterone levels. Besides that, mice with a deleted Il6 (IL6KO) showed increased testicular SOCS3 levels, with no changes in pJAK/JAK and pSTAT3/STAT3 ratios. It is worth noting that the aforementioned pathway is not the only pathway to up-regulate SOCS3, nor is it the only SOCS3 target, thus proposing that the increase of SOCS3 in the testis occurs independently of the JAK-STAT signaling in IL6KO mice. Therefore, we suggest that the lack of Il6 drives androgenic production by increasing SOCS3 in the testis, thus leading to an increase in spermatogenesis.

Paternal exercise protects against liver steatosis in the male offspring of mice submitted to high fat diet.

Parental lifestyle has been related to alterations in the phenotype of their offspring. Obese sires can induce offspring insulin resistance as well as increase susceptibility to obesity. On the other hand, obese sires submitted to voluntary exercise ameliorate the deleterious metabolic effects on their offspring. However, there are no studies reporting the effect of programmed exercise training of lean sires on offspring metabolism. AIMS: This study aimed to investigate the role of swimming training of sires for 6 weeks on the offspring metabolic phenotype. MAIN METHODS: Male C57BL/6 mice fed a control diet were divided into sedentary and swimming groups. After the exercise, they were mated with sedentary females, and body weight and molecular parameters of the offspring were subsequently monitored. KEY FINDINGS: Swimming decreased the gene expression of Fasn and Acaca in the testes and increased the AMPK protein content in the testes and epididymis of the sires. The progeny presented a low weight at P1, which reached a normal level at P60 and at P90 the animals were challenged with HFD for 16 weeks. The male offspring of trained sires presented less body weight gain than the control group. The level of steatosis decreased in the male offspring from trained sires. The gene expression of Prkaa2, Ppar-1α and Cpt-1 was also increased in the liver of male offspring from trained sires. SIGNIFICANCE: Taken together, these findings suggest that paternal exercise training can improve the metabolic profile in the liver of the progeny, thereby ameliorating the effects of obesity.

Physical Exercise Exacerbates Acute Kidney Injury Induced by LPS via Toll-Like Receptor 4.

Introduction: Lipopolysaccharide (LPS) is a systemic response-triggering endotoxin, which has the kidney as one of its first targets, thus causing acute injuries to this organ. Physical exercise is capable of promoting physiological alterations and modulating inflammatory responses in the infectious process through multiple parameters, including the toll-like receptor (TLR)-4 pathway, which is the main LPS signaling in sepsis. Additionally, previous studies have shown that physical exercise can be both a protector factor and an aggravating factor for some kidney diseases. This study aims at analyzing whether physical exercise before the induction of LPS endotoxemia can protect kidneys from acute kidney injury. Methods: C57BL/6J male mice, 12 weeks old, were distributed into four groups: (1) sedentary (control, N = 7); (2) sedentary + LPS (N = 7); (3) trained (N = 7); and (4) trained + LPS (N = 7). In the training groups, the animals exercised 5×/week in a treadmill, 60 min/day, for 4 weeks (60% of max. velocity). Sepsis was induced in the training group by the application of a single dose of LPS (5 mg/kg i.p.). Sedentary animals received LPS on the same day, and the non-LPS groups received a saline solution instead. All animals were euthanized 24 h after the administration of LPS or saline. Results: The groups receiving LPS presented a significant increase in serum urea (p < 0.0001) and creatinine (p < 0.001) concentration and renal gene expression of inflammatory markers, such as tumor necrosis factor alpha and interleukin-6, as well as TLRs. In addition, LPS promoted a decrease in reduced glutathione. Compared to the sedentary + LPS group, trained + LPS showed overexpression of a gene related to kidney injury (NGAL, p < 0.01) and the protein levels of LPS receptor TLR-4 (p < 0.01). Trained + LPS animals showed an expansion of the tubulointerstitial space in the kidney (p < 0.05) and a decrease in the gene expression of hepatic AOAH (p < 0.01), an enzyme involved in LPS clearance. Conclusion: In contrast to our hypothesis, training was unable to mitigate the renal inflammatory response caused by LPS. On the contrary, it seems to enhance injury by accentuating endotoxin-induced TLR-4 signaling. This effect could be partly due to the modulation of a hepatic enzyme that detoxifies LPS.

Nephropathy in Hypertensive Animals Is Linked to M2 Macrophages and Increased Expression of the YM1/Chi3l3 Protein.

Macrophages contribute to a continuous increase in blood pressure and kidney damage in hypertension, but their polarization status and the underlying mechanisms have not been clarified. This study revealed an important role for M2 macrophages and the YM1/Chi3l3 protein in hypertensive nephropathy in a mouse model of hypertension. Bone marrow cells were isolated from the femurs and tibia of male FVB/N (control) and transgenic hypertensive animals that overexpressed the rat form of angiotensinogen (TGM(rAOGEN)123, TGM123-FVB/N). The cells were treated with murine M-CSF and subsequently with LPS+IFN-γ to promote their polarization into M1 macrophages and IL-4+IL-13 to trigger the M2 phenotype. We examined the kidneys of TGM123-FVB/N animals to assess macrophage polarization and end-organ damage. mRNA expression was evaluated using real-time PCR, and protein levels were assessed through ELISA, CBA, Western blot, and immunofluorescence. Histology confirmed high levels of renal collagen. Cells stimulated with LPS+IFN-γ in vitro showed no significant difference in the expression of CD86, an M1 marker, compared to cells from the controls or the hypertensive mice. When stimulated with IL-4+IL-13, however, macrophages of the hypertensive group showed a significant increase in CD206 expression, an M2 marker. The M2/M1 ratio reached 288%. Our results indicate that when stimulated in vitro, macrophages from hypertensive mice are predisposed toward polarization to an M2 phenotype. These data support results from the kidneys where we found an increased infiltration of macrophages predominantly polarized to M2 associated with high levels of YM1/Chi3l3 (91,89%), suggesting that YM1/Chi3l3 may be a biomarker of hypertensive nephropathy.