Epididymal Fat-Derived Sympathoexcitatory Signals Exacerbate Neurogenic Hypertension in Obese Male Mice Exposed to Early Life Stress

Previously, we have shown that male mice exposed to maternal separation and early weaning (MSEW)—a mouse model of early life stress—display increased mean arterial pressure compared with controls when fed a high-fat diet. As the stimulation of sensory nerves from fat has been shown to trigger the adipose afferent reflex, we tested whether MSEW male mice show obesity-associated hypertension via the hyperactivation of this sympathoexcitatory mechanism. After 16 weeks on high-fat diet, MSEW mice displayed increased blood pressure, sympathetic activation, and greater depressor response to an α-adrenergic blocker when compared with controls ( P <0.05; n=8), despite no differences in adiposity and plasma leptin. The acute infusion of capsaicin in epididymal white adipose tissue (1.5 pmol/μL of capsaicin, 8 μL/per site, 4 sites, bilaterally) increased the total pressor response in MSEW mice compared with controls (110±19 versus 284±33 mm Hg×30 minutes; P <0.05; n=8). This response was associated with neuronal activation in OVLT, posterior paraventricular nucleus of the hypothalamus, and RVLM ( P <0.05 versus control; n=6–7). Renal denervation abolished both the acute and chronic elevated mean arterial pressure in obese MSEW mice. Moreover, selective sensory denervation of epididymal white adipose tissue using resiniferatoxin (10 pmol/µL solution; n=6) decreased mean arterial pressure in obese MSEW mice only ( P <0.05 versus control). Obese MSEW mice displayed increased epididymal white adipose tissue levels of both tryptophan hydroxylase (Tph1) mRNA expression and its synthesis product serotonin (8.3±1.9 versus 16.6±1.7 ug/mg tissue; P <0.05 versus control). Thus, afferent sensory signals from epididymal white adipose tissue may contribute to the exacerbated fat–brain–blood pressure axis displayed by obese male mice exposed to early life stress.

CX3CL1–CX3CR1 signalling deficiency exacerbates obesity-induced inflammation and insulin resistance in male mice

The CX3CL1–CX3CR1 system plays an important role in disease progression by regulating inflammation both positively and negatively. We reported previously that C-C chemokine receptor 5, as well as CCR2, promotes obesity-associated adipose tissue inflammation and insulin resistance. Here, we demonstrate that CX3CL1–CX3CR1 signalling is involved in adipose tissue inflammation and insulin resistance in obese mice, via adipose tissue macrophage recruitment and M1/M2 polarization. CX3CL1 expression was persistently decreased in the epididymal white adipose tissue (eWAT) of high-fat diet-induced obese (DIO) mice, despite increased expression of other chemokines. Interestingly, in Cx3cr1 −/− mice, glucose tolerance, insulin resistance, and hepatic steatosis induced by DIO or leptin deficiency were exacerbated. CX3CL1–CX3CR1 signalling deficiency resulted in reduced M2-polarized macrophage migration and an M1-dominant shift of macrophages within eWAT. Furthermore, transplantation of Cx3cr1 −/− bone marrow was sufficient to impair glucose tolerance, insulin sensitivity, and regulation of M1/M2 status. Moreover, CX3CL1 administration in vivo led to the attenuation of glucose intolerance and insulin resistance. Thus, therapy targeting the CX3CL1–CX3CR1 system may be beneficial in the treatment of type 2 diabetes by regulating M1/M2 macrophages.

Butaphosphan Effects on Glucose Metabolism Involve Insulin Signaling and Depends on Nutritional Plan

Butaphosphan is an organic phosphorus compound used in several species for the prevention of rapid catabolic states, however, the mechanism of action remains unclear. This study aimed at determining the effects of butaphosphan on energy metabolism of mice receiving a normal or hypercaloric diet (HCD) and submitted or not to food restriction. Two experiments were conducted: (1) during nine weeks, animals were fed with HCD (n = 28) ad libitum, and at the 10th week, were submitted to food restriction and received butaphosphan (n = 14) or saline injections (n = 14) (twice a day, for seven days) and; (2) during nine weeks, animals were fed with a control diet (n = 14) or HCD (n = 14) ad libitum, and at the 10th week, all animals were submitted to food restriction and received butaphosphan or saline injections (twice a day, for seven days). In food restriction, butaphosphan preserved epididymal white adipose tissue (WAT) mass, increased glucose, NEFA, and the HOMA index. In mice fed HCD and submitted to food restriction, the butaphosphan preserved epididymal WAT mass. Control diet influences on PI3K, GCK, and Irs1 mRNA expression. In conclusion, butaphosphan increased blood glucose and reduced fat mobilization in overweight mice submitted to caloric restriction, and these effects are influenced by diet.

Supplementation of Bacillus amyloliquefaciens AS385 culture broth powder containing 1-deoxynojirimycin in a high-fat diet altered the gene expressions related to lipid metabolism and insulin signaling in mice epididymal white adipose tissue

Supplementation of Bacillus amyloliquefaciens AS385 culture broth powder in high-fat diet restored adiposity, glucose tolerance and insulin sensitivity in mice.