really interesting abstract. Bisphenol A (BPA) is a xenoestrogen. This animal study finds that BPA down regulated ER-beta in the brains of male rats. It also blocked the production of GABA(A)alpha 2 receptor. These long term effects were evident in anxiety and depression in adult mice.
Pregnancy exposure would set up an ER-alpha dominance in the male brain increasing risk of continuous ER alpha stim.
C. leptum, C. coccoides, Bacteroides and Bifidobacterium represent the four dominant groups of the adult fecal microbiota
Lactobacilli Enterobacteriaceae, Desulfovibrio, Sporomusa, Atopobium as well as other bacterial groups including Clostridium clusters XI, XIVb, and XVIII
The Firmicutes/Bacteroidetes ratio undergoes an increase from birth to adulthood and is further altered with advanced age
Activation of inflammatory pathways in adipocytes impairs triglyceride storage and increases release of free fatty acids, an excess of which is known to induce insulin resistance in muscle and liver
recent studies have shown that large numbers of macrophages infiltrate obese adipose tissue,
It has been postulated that a paracrine loop involving free fatty acids and inflammatory cytokines establishes a vicious cycle between adipocytes and macrophages that propagates the inflammation
not only does interrupting the accumulation of macrophages within obese adipose tissue suppresses adipose inflammation in various animal models, it also ameliorates systemic insulin resistance and metabolic abnormalities, suggesting macrophages are key effector cells involved in adipose inflammation
activation of the leukocyte adhesion cascade, a hallmark of inflammation
Thus, obese visceral adipose tissue is clearly a site of chronic inflammation
CD8+ T cells within obese adipose tissue induce activation and migration of monocytes/macrophages, and in cooperation with the adipose tissue, they also induce macrophage differentiation. At the same time, obese adipose tissue activates CD8+ T cells, creating a vicious cycle involving CD8+ T cells, macrophages, and obese adipose tissue that propagates local inflammation
In obese adipose tissue there is a shift to dominance of CD8+ and TH1 T cells, which appears to propagate inflammation
diacylglycerol O-acyltransferase 2 (DGAT2), mechanistically implicated in this differential storage, [10] is regulated by dihydrotestosterone, [11] suggesting a potential role for androgens to influence the genetic predisposition to either the MHO or MONW phenotype.
bariatric surgery achieves 10%-30% long-term weight loss in controlled studies
The fact that obese men have lower testosterone compared to lean men has been recognized for more than 30 years
Reductions in testosterone levels correlate with the severity of obesity and men
epidemiological data suggest that the single most powerful predictor of low testosterone is obesity, and that obesity is a major contributor of the age-associated decline in testosterone levels.
healthy ageing by itself is uncommonly associated with marked reductions in testosterone levels
obesity blunts this LH rise, obesity leads to hypothalamic-pituitary suppression irrespective of age which cannot be compensated for by physiological mechanisms
Reductions in total testosterone levels are largely a consequence of reductions in sex hormone binding globulin (SHBG) due to obesity-associated hyperinsulinemia
although controversial, measurement of free testosterone levels may provide a more accurate assessment of androgen status than the (usually preferred) measurement of total testosterone in situations where SHBG levels are outside the reference range
SHBG increases with age
marked obesity however is associated with an unequivocal reduction of free testosterone levels, where LH and follicle stimulating hormone (FSH) levels are usually low or inappropriately normal, suggesting that the dominant suppression occurs at the hypothalamic-pituitary level
adipose tissue, especially when in the inflamed, insulin-resistant state, expresses aromatase which converts testosterone to estradiol (E 2 ). Adipose E 2 in turn may feedback negatively to decrease pituitary gonadotropin secretion
diabetic obesity is associated with decreases in circulatory E 2
In addition to E 2 , increased visceral fat also releases increased amounts of pro-inflammatory cytokines, insulin and leptin; all of which may inhibit the activity of the HPT axis at multiple levels
In the prospective Massachusetts Male Aging Study (MMAS), moving from a non-obese to an obese state resulted in a decline of testosterone levels
weight loss, whether by diet or surgery, increases testosterone levels proportional to the amount of weight lost
fat is androgen-responsive
low testosterone may augment the effects of a hypercaloric diet
In human male ex vivo adipose tissue, testosterone decreased adipocyte differentiation by 50%.
Testosterone enhances catecholamine-induced lipolysis in vitro and reduces lipoprotein lipase activity and triglyceride uptake in human abdominal adipose tissue in vivo
in men with prostate cancer receiving 12 months of androgen deprivation therapy, fat mass increased by 3.4 kg and abdominal VAT by 22%, with the majority of these changes established within 6 months
severe sex steroid deficiency can increase fat mass rapidly
bidirectional relationship between testosterone and obesity
increasing body fat suppresses the HPT axis by multiple mechanisms [30] via increased secretion of pro-inflammatory cytokines, insulin resistance and diabetes; [19],[44] while on the other hand low testosterone promotes further accumulation of total and visceral fat mass, thereby exacerbating the gonadotropin inhibition
androgens may play a more significant role in VAT than SAT
men undergoing androgen depletion for prostate cancer show more marked increases in visceral compared to subcutaneous fat following treatment
Interesting: low T increases VAT, yet T therapy does not reduce VAT, yet T therapy reduces SAT.
irisin, derived from muscle, induces brown fat-like properties in rodent white fat
androgens can act via the PPARg-pathway [37] which is implicated in the differentiation of precursor fat cells to the energy-consuming phenotype
low testosterone may compound the effect of increasing fat mass by making it more difficult for obese men to lose weight via exercise
pro-inflammatory cytokines released by adipose tissue may contribute to loss of muscle mass and function, leading to inactivity and further weight gain in a vicious cycle
Sarcopenic obesity, a phenotype recapitulated in men receiving ADT for prostate cancer, [55] may not only be associated with functional limitations, but also aggravate the metabolic risks of obesity;
observational evidence associating higher endogenous testosterone with reduced loss of muscle mass and crude measures of muscle function in men losing weight
genuine reactivation of the HPT axis in obese men requires more substantial weight-loss
A number of intervention studies have confirmed that both diet- and surgically-induced weight losses are associated with increased testosterone, with the rise in testosterone generally proportional to the amount of weight lost
men, regardless of obesity level, can benefit from the effect of weight loss.
Testosterone was inversely associated with weight and age. This study points to this as the primary driver of low T, even in Diabetics. Total Testosterone was inversely associated with BMI and free (calculated) Testosterone was associated with age.
This study finds that BMI and age are driving forces of low Testosterone. This study did not find that Diabetes was significantly associated with decreasing Testosterone levels.
Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression
imbalance of their expression may be critical to determine the ultimate estrogen effects on prostate cancer cells
In prostate cancer, ERβ activation appears to limit cell proliferation directly or through ERα inhibition, and loss of ERβ has been consistently associated with tumor progression
Nice study. This study tries to get to the source of problem. The authors of this study found that low T in men is more associated with increasing BMI and age versus the presence of diabetes.
ER-beta expression appears to regulate estrogenic activity through ER-alpha expression. Co-expression of ER-alpha and ER-beta is associated with reduced estrogenic signaling, indicating a significant counter regulatory role for ER-beta.
he gut microbiota enhances the host’s metabolic capacity for processing nutrients and drugs and modulate the activities of
multiple pathways in a variety of organ systems.
Acquisition of the gut microbiota was associated with rapid increase in body weight (4%) over the first 5 days of
colonization
The colonization process stimulated
glycogenesis in the liver prior to triggering increases in hepatic triglyceride synthesis
modifications of hepatic Cyp8b1 expression and the subsequent alteration of bile acid metabolites
Expression and activity of major drug-metabolizing
enzymes (Cyp3a11 and Cyp2c29) were also significantly stimulated
The gut microbiota (GM) exhibits a relatively low level of diversity compared to those of most soil ecosystems and in humans
it is comprised of usually no more than nine phyla of microorganisms, of which only two are dominant: the Firmicutes and the Bacteroidetes
colonization of a germfree gut was rapid and remarkably stable, establishing within only
a week after first exposure
a study conducted on germfree rats by Nicholls et al. showed that 3 weeks were necessary
to obtain a stabilization and “normalization”
the microbiota status affects
the systemic metabolism of the host, modulating the metabolic fingerprint of topographically remote organs such as the liver
and the kidney
Gut colonization induces a rapid weight gain associated with stimulation of hepatic glycogenesis and triglyceride synthesis
Gut colonization alters bile acid metabolite profiles via modulation of hepatic Cyp8b1 expression
Bile acids are well-known contributors to glucose and lipid metabolism in the liver
GM is known to alter bile metabolism
GM is also known to exert a strong influence on the metabolism of xenobiotics
The effects of gut microbiome are not confined to the gut. They alter bile acid metabolism and thus lipid/glucose metabolism. They alter CYP450 activity. They effect metabolism. They effect the metabolism, and thus effects, of other drugs.
Studies in both humans and rodents, however, suggest that low testosterone is due to age-related lesions in testes rather than irregular luteinizing hormone metabolism
Various dietary factors and diet-induced obesity have been shown to increase the risk for late onset male hypogonadism and low testosterone production in both humans and mice
Testosterone deficiency and metabolic diseases such as obesity appear to inter-digitate in complex cause-and-effect relationships
dietary supplementation of aged mice with the probiotic bacterium Lactobacillus reuteri makes them appear to be younger than their matched untreated sibling mice
These results indicate that gut microbiota induce modulation of local gastrointestinal immunity resulting in systemic effects on the immune system which activate metabolic pathways that restore tissue homeostasis and overall health
all these studies we consistently observed that young and aged mice consuming purified L. reuteri organisms had particularly large testes and a dominant male behavior.
The testes of probiotic-fed aged mice were rescued from both seminiferous tubule atrophy and interstitial Leydig cell area reduction typical of the normal aging process. Preservation of testicular architecture despite advanced age or high-fat diet coincided with remarkably high levels of circulating testosterone. The beneficial effects of probiotic consumption were recapitulated by the depletion of the pro-inflammatory cytokine Il-17.
feeding of L. reuteri consistently increased the gonadal weights, consumption of a non-pathogenic strain of Escherichia coli (E. coli) K12 organisms did not affect testicular weight
mice with dietary L. reuteri supplements were rescued from diet-induced obesity and had normal body weight and lean physique
Despite the comparable numbers of ST profiles, we determined that testes from L. reuteri-treated mice had increased ST cross-sectioned profiles
the probiotic organism induced prominent Leydig cell accumulations in the interstitial tissue between the ST's
The probiotic-associated increase of interstitial Leydig cell areas was sustained with advancing age at 7 (CD vs CD+LR, P = 0.0025; CD+E.coli vs CD+LR, P = 0.0251) and 12 months
mice eating L. reuteri had profoundly increased levels of circulating testosterone regardless of the type of diet they consumed
blocking pro-inflammatory Il-17 signaling entirely recapitulates the beneficial effects of probiotics
previous studies we found that dietary probiotics counteract obesity [19] and age-related integumentary pathology [18] at least in part by down-regulating systemic pro-inflammatory IL-17A-dependent signaling
Testes histomorphometry and serum androgen concentration data were both suggestive of a probiotic-associated up-regulation of spermatogenesis in mice
Lactobacillus reuteri we discovered that aging male animals had larger testes compared to their age-matched controls
xamined testes of probiotic microbe-fed mice and found that they had less testicular atrophy coinciding with higher levels of circulating testosterone compared to their age-matched controls
Similar testicular health benefits were produced using systemic depletion of the pro-inflammatory cytokine Il-17 alone, implicating a chronic inflammatory pathway in hypogonadism
One specific aspect of this paradigm is reciprocal activities of pro-inflammatory Th-17 and anti-inflammatory Treg cells
Feeding of L. reuteri organisms was previously shown to up-regulate IL-10 levels and reduce levels of IL-17 [19] serving to lower systemic inflammation
insufficient levels of IL-10 may increase the risk for autoimmunity, obesity, and other inflammatory disease syndromes
Westernized diets are also low in vitamin D, a nutrient that when present normally works together with IL-10 to protect against inflammatory disorders
Physiological feedback loops apparently exist between microbes, host hormones, and immunity
The hormone testosterone has been shown to act directly through androgen receptors on CD4+ cells to increase IL-10 expression
studies in both humans and rodents suggest that hypogonadism is due to age-related lesions in testes rather than irregular LH metabolism
We postulate that probiotic gut microbes function symbiotically with their mammalian hosts to impart immune homeostasis to maintain systemic and testicular health [34]–[35] despite suboptimal dietary conditions.
Dietary factors and diet-induced obesity were previously shown to increase risk for age-associated male hypogonadism, reduced spermatogenesis, and low testosterone production in both humans and mice [2]–[4], [8]–[11], [14]–[17], phenotypic features that in this study were inhibited by oral probiotic therapy absent milk sugars, extra protein, or vitamin D supplied in yogurt.
Similar beneficial effects of probiotic microbes on testosterone levels and sperm indices were reported in male mice that had been simultaneously supplemented with selenium
L. reuteri-associated prevention of age- and diet-related testicular atrophy correlates with increased numbers and size of Leydig cells
the initial changes of testicular atrophy begin to occur in mice from the age of 6 moths onwards [7] and indicates that the trophic effect of L. reuteri on Leydig cells is a key event which precedes and prevents age-related changes in the testes of mice. This effect is reminiscent of earlier studies describing Leydig cell hyperplasia and/or hypertrophy in the mouse and the rat testis that were achievable by the administration of gonadotropins, including human chorionic gonadotropin, FSH and LH
Fascinating study on how the addition of Lactobacillus reuteri increased Testicular size, prevented testicular atrophy, increased serum Testosterone production and protected against diet-induced/obesity-induced hypogonadism. This was a mouse model
The gut microbiota participates in the body’s metabolism by affecting energy balance, glucose metabolism, and low-grade inflammation associated with obesity and related metabolic disorders
Firmicutes and Bacteroidetes represent the two largest phyla in the human and mouse microbiota and a shift in the ratio of these phyla has been associated with many disease conditions, including obesity
In obese humans, there is decreased abundance of Bacteroidetes compared to lean individuals
weight loss in obese individuals results in an increase in the abundance of Bacteroidetes
there is conflicting evidence on the composition of the obese microbiota phenotype with regards to Bacteroidetes and Firmicutes ratios
Bifidobacteria spp. from the phyla Actinobacteria, has been shown to be depleted in both obese mice and human subjects
While it is not yet clear which specific microbes are inducing or preventing obesity, evidence suggests that the microbiota is a factor.
targeted manipulation of the microbiota results in divergent metabolic outcomes depending on the composition of the diet
The microbiota has been linked to insulin resistance or type 2 diabetes (T2D) via metabolic syndrome and indeed the microbiota of individuals with T2D is also characterized by an increased Bacteroidetes/Firmicutes ratio, as well as an increase in Bacillus and Lactobacillus spp
It was also observed that the ratio of Bacteriodes-Prevotella to C. coccoides-E. rectale positively correlated with glucose levels but did not correlate with body mass index [80]. This suggests that the microbiota may influence T2D in conjunction with or independently of obesity
In humans, high-fat Western-style diets fed to individuals over one month can induce a 71% increase in plasma levels of endotoxins, suggesting that endotoxemia may develop in individuals with GI barrier dyfunction connected to dysbiosis
LPS increases macrophage infiltration essential for systemic inflammation preceding insulin resistance, LPS alone does not impair glucose metabolism
early treatment of dysbiosis may slow down or prevent the epidemic of metabolic diseases and hence the corresponding lethal cardiovascular consequences
increased Firmicutes and decreased Bacteroidetes, which is the microbial profile found in lean phenotypes, along with an increase in Bifidobacteria spp. and Lactobacillus spp
mouse and rat models of T1D have been shown to have microbiota marked by decreased diversity and decreased Lactobacillus spp., as well as a decrease in the Firmicutes/Bacteroidetes ratio
microbial antigens through the innate immune system are involved in T1D progression
The microbiota appears to be essential in maintaining the Th17/Treg cell balance in intestinal tissues, mesenteric and pancreatic lymph nodes, and in developing insulitis, although progression to overt diabetes has not been shown to be controlled by the microbiota
There is evidence that dietary and microbial antigens independently influence T1D
Lactobacillus johnsonii N6.2 protects BB-rats from T1D by mediating intestinal barrier function and inflammation [101,102] and a combination probiotic VSL#3 has been shown to attenuate insulitis and diabetes in NOD mice
breast fed infants have higher levels of Bifidobacteria spp. while formula fed infants have higher levels of Bacteroides spp., as well as increased Clostridium coccoides and Lactobacillus spp
the composition of the gut microbiota strongly correlates with diet
In mice fed a diet high in fat, there are many key gut population changes, such as the absence of gut barrier-protecting Bifidobacteria spp
diet has a dominating role in shaping gut microbiota and changing key populations may transform healthy gut microbiota into a disease-inducing entity
“Western” diet, which is high in sugar and fat, causes dysbiosis which affects both host GI tract metabolism and immune homeostasis
a decreasing Testosterone:Estradiol ratio leads to decreased sperm production. This effectively occurs through the interaction of the elevated Estradiol and the HPA.
It is estimated that approximately 30% of children and adolescents in the United States and about 15–30% of those in Europe can be classified as overweight or obese
An increasing body of evidence now suggests that the nutritional environment encountered in utero and the early postnatal life may elicit permanent alterations in adipose tissue structure or function and, thereby, programme the individual’s propensity to later obesity
The composition of fatty acids in the Western diets has shifted toward an increasing dominance of n-6 relative to n-3 LCPUFAs over the past decades.9,10 This shift is also reflected in the fatty acid composition of breast milk
Evidence from animal studies suggests that the n-6 LCPUFA arachidonic acid promotes adipose tissue deposition, whereas the n-3 LCPUFAs eicosapentaenoic acid and docosahexaenoic acid seem to exert an opposite effect
Overall, no effect of supplementation was found on BMI in preschool (<5 years) and school-aged (6–12 years) children
increased adiposity, once established in childhood, tends to track into adulthood
Many studies have shown that even children <2 years with a high BMI are at increased risk of developing obesity later in life
The acquisition of fat cells early in life appears to be an irreversible process
Evidence from cell culture and animal studies suggests that early exposure to n-3 LCPUFAs has the potential to limit adipose tissue deposition mainly by attenuating the production of the arachidonic acid metabolite prostacyclin, which has been shown to enhance adipogenesis
In conclusion, there is currently no evidence to support that maternal n-3 LCPUFA supplementation during pregnancy and/or lactation exerts a favourable programming effect on adiposity status in childhood
our systematic review highlights that most of the trials reviewed were prone to methodological limitations
Literature review finds limited data (9 studies, only 6 RCTs) of omega-3 during pregnancy. No data was found that supported reduced obesity in children by mothers taking n-3 during pregnancy. No harm was found either. Data was sparse.
Take home: not enough data, no harm to pregnancy, children, thus if indications are present for mother, then recommend n-3. At this point not studies have pointed to reduced obesity in children.
The relationship of low testosterone to MetS often is considered to be bidirectional; however, the relationships probably are not direct
Many of the components of the MetS are recognized risk factors for the development of cardiovascular disease (CVD)
Multiple cross-sectional studies have found low TT and low sex hormone binding globulin (SHBG) levels in Caucasian and African-American men with the MetS, irrespective of age
Low TT and SHBG levels also are prevalent in Chinese [7],[8] and Korean [9] men with the MetS
Normally 40%-50% of TT is bound to SHBG, so reducing SHBG levels will decrease TT.
Hyperinsulinism suppresses SHBG synthesis and secretion by the liver
significant increase in SHBG levels occurred after acutely lowering insulin levels in obese men
Estradiol levels are increased in men with the MetS, and they are positively correlated with the number of abnormal components of the MetS.
Although it is known that estrogen will increase SHBG levels, apparently the hyperinsulinism associated with obesity has a greater effect on SHBG levels
Estradiol also can inhibit luteinizing hormone (LH) secretion
Inflammatory cytokines are thought to have a direct effect on the pituitary to reduce LH secretion [15] and also a direct effect on Leydig cell secretion of testosterone
Low TT Levels have been shown to predict development of the MetS in men with normal BMI
Men in the lowest quartiles of serum TT, calculated free testosterone (cFT) and SHBG at baseline had the highest odds ratios for developing the MetS or DM during the 11 years follow-up
More recently, investigators conducting population-based studies have reported that only SHBG is associated with future development of the MetS
Additional evidence that low TT increases the risk of MetS comes from androgen deprivation treatment of prostate cancer
Low TT and low bioavailable testosterone (bT) were each significantly associated with elevated 20 years risk of CVD mortality in an older population in which cause-specific mortality was age, adiposity, and lifestyle-adjusted.
combination of low bT and ATP III-defined MetS is associated with increased cardiovascular mortality in men aged 40 years and above
in elderly men, testosterone may weakly protect against CVD. Alternatively, low TT may indicate poor general health
Muraleedharan and Jones [27] concluded that there is convincing evidence that low T is a biomarker for disease severity and mortality.
The evidence that TRT improves insulin sensitivity and glucose control is conflicted
It is widely recognized that testosterone treatment can reduce fat mass and increase lean body mass; however, until recently most reports have not been associated with much weight loss
Changes in body composition and weight loss are considered potential mechanisms by which testosterone treatment improves insulin sensitivity and glucose control in patients with diabetes. Effects on inflammatory cytokines [38] and changes in oxidative metabolism [39] also have been reported to improve glucose metabolism.
Testosterone replacement therapy has been reported to improve some or all of the components of the MetS.
Nice study of Chinese men, only abstract available, finds that serum total Testosterone and SHBG were inversely associated with metabolic syndrome in men. SHBG association was the strongest and TT the weakest. Free Testosterone had no association in this study.