A subsequent study by Yuan et al. showed that Tnf treatment of 3T3L1 adipocytes induces insulin resistance and that this could be prevented by pretreatment of cells with aspirin
Activation of the Tnf receptor results in stimulation of NFκB signaling via Ikkb
the percentage of macrophages in a given adipose tissue depot is positively correlated with adiposity and adipocyte size
Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes
Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NFκB activation by reducing IKK activity [38]
adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression
One theory holds that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia and that large adipocytes outstrip the local oxygen supply leading to cell autonomous hypoxia with activation of cellular stress pathways
The use of the anti-inflammatory compounds, salicylate and its derivative aspirin, for treating symptoms of T2DM dates back over 100 years
elevated levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states
overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses
Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity
In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter
macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the “classically activated” pro-inflammatory macrophage, to the M2 state or the “alternatively activated” non-inflammatory cell
saturated fatty acids are the most potent inducers of this inflammatory response
Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes iNOS (reviewed in [33]
Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production
elevated JNK activity in liver, adipose tissue and skeletal muscle of obese insulin resistant mice, and knockout of Jnk1 (Jnk1−/−) leads to amelioration of insulin resistance in high fat diet
Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance
C-reactive protein (CRP)
these studies highlight the possibility that increased iNOS activity plays a direct role in the pathogenesis of insulin resistance
the important role of Ikkb in the development of obesity and inflammation-induced insulin resistance.
It is probable that local concentrations of inflammatory mediators, such as FFAs, Tnf or other cytokines/adipokines contribute to this polarity switch
Tnf and other cytokines/chemokines are symptomatic of inflammation, and while they propagate and/or maintain the inflammatory state, they are not the initial cause(s) of inflammation
Tlr4, in particular, is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria
Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system.
Tlr4 stimulation results in the activation of both Ikkb/NFκB and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1, etc. (reviewed in [57
secretion of MCP-1,
resistin, and other proinflammatory cytokines is increased by
obesity, the adipose secretion of the anti-inflammatory protein
adiponectin is decreased
the
peroxisome proliferators- activated receptor (PPAR) family are
involved in the regulation of inflammation and energy homestasis
natural agonists, including unsaturated fatty acids and
eicosanoids
PPARα also
regulates inflammatory processes, mainly by inhibiting
inflammatory gene expression
upregulation of COX-2 is seen in alcoholic
steatohepatitis and nonalcoholic steatohepatitis and has been
directly linked to the progression of steatosis to
steatohepatitis, the inhibitory effect of PPARα on COX-2
may reduce steatohepatitis
PPARα agonists have a clear anorexic
effect resulting in decreased food intake, evidence is
accumulating that PPARα may also directly influence
adipose tissue function, including its inflammatory
status.
PPARα may govern adipose tissue inflammation in three
different ways: (1) by decreasing adipocyte hypertrophy, which is
known to be connected with a higher inflammatory status of the
tissue [3, 11, 59], (2) by direct regulation of inflammatory
gene expression via locally expressed PPARα, or (3) by
systemic events likely originating from liver
PPARγ is considered the master regulator of adipogenesis
Unsaturated fatty acids and several
eicosanoids serve as endogenous agonists of PPARγ
PPARγ2, which is
adipose-tissue specific
two different molecular mechanisms have been proposed by which
anti-inflammatory actions of PPARγ are effectuated: (1)
via interference with proinflammatory transcription factors
including STAT, NF-κB, and AP-1
and (2) by preventing removal of corepressor complexes from gene promoter
regions resulting in suppression of inflammatory gene
transcription
diet-induced obesity is associated with increased inflammatory
gene expression in adipose tissue via adipocyte hypertrophy and
macrophage infiltration
PPARγ is
able to reverse macrophage infiltration, and subsequently reduces
inflammatory gene expression
Inflammatory adipokines mainly originate from macrophages which
are part of the stromal vascular fraction of adipose tissue
[18, 19], and accordingly, the downregulation of inflammatory
adipokines in WAT by PPARγ probably occurs via effects on
macrophages
By interfering with NF-κB signaling pathways,
PPARγ is known to decrease inflammation in activated
macrophages
Recent data suggest that activation of PPARγ in
fatty liver may protect against inflammation
PPARs may influence the inflammatory response either by direct
transcriptional downregulation of proinflammatory genes
anti-inflammatory
properties of PPARs in human obesity
PPARs play pivotal in obesity. PPARs appear to reduce the inflammatory cascade associated with obesity. Downregulation of PPARs are associated with increased inflammation. Natural PPARs include unsaturated fats and eicosanoids.
berberine reduces leptin and fat in humans. It also improves insulin sensitivity and reduces insulin levels. This study also found a decrease in adiponectin.
fat and obesity becomes a hormone, inflammatory producing organ. Great read. You must be healthy to lose weight, not lose weigh to be healthy. The "fat" in obesity has been link to many of the chronic diseases of aging
The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time
It is clear that inflammation participates in the link between obesity and disease
Multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines (10), decreases in protective factors (e.g., adiponectin; ref. 11), and communication between inflammatory and metabolic cells
adipose tissue macrophage (ATM)
Physiologic enhancement of the M2 pathways (e.g., eosinophil recruitment in parasitic infection) also appears to be capable of reducing metainflammation and improving insulin sensitivity (27).
increasing adiposity results in a shift in the inflammatory profile of ATMs as a whole from an M2 state to one in which classical M1 proinflammatory signals predominate (21–23).
The M2 activation state is intrinsically linked to the activity of PPARδ and PPARγ
well-known regulators of lipid metabolism and mitochondrial activity
Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension (63–65).
inflammation in pancreatic islets can reduce insulin secretion and trigger β cell apoptosis leading to decreased islet mass, critical events in the progression to diabetes (33, 34)
Since an estimated excess of 20–30 million macrophages accumulate with each kilogram of excess fat in humans, one could argue that increased adipose tissue mass is de facto a state of increased inflammatory mass
JNK, TLR4, ER stress)
NAFLD is associated with an increase in M1/Th1 cytokines and quantitative increases in immune cells
Upon stimulation by LPS and IFN-γ, macrophages assume a classical proinflammatory activation state (M1) that generates bactericidal or Th1 responses typically associated with obesity
DIO, metabolites such as diacylglycerols and ceramides accumulate in the hypothalamus and induce leptin and insulin resistance in the CNS (58, 59)
saturated FAs, which activate neuronal JNK and NF-κB signaling pathways with direct effects on leptin and insulin signaling (60)
Lipid infusion and a high-fat diet (HFD) activate hypothalamic inflammatory signaling pathways, resulting in increased food intake and nutrient storage (57)
Maternal obesity is associated with endotoxemia and ATM accumulation that may affect the developing fetus (73)
Placental inflammation is a characteristic of maternal obesity
a risk factor for obesity in offspring, and involves inflammatory macrophage infiltration that can alter the maternal-fetal circulation (74
Of these PRRs, TLR4 has received the most attention, as this receptor can be activated by free FAs to generate proinflammatory signals and activate NF-κB
Nod-like receptor (NLR) family of PRRs
ceramides and sphingolipids
The adipokine adiponectin has long been recognized to have positive benefits on multiple cell types to promote insulin sensitivity and deactivate proinflammatory pathways.
adiponectin stimulates ceramidase activity and modulates the balance between ceramides and sphingosine-1-phosphate
Inhibition of ceramide production blocks the ability of saturated FAs to induce insulin resistance (101)
NF-κB, obesity also activates JNK in insulin-responsive tissues
Hypogonadism and MetS are strongly associated [12, 13, 16], having even been demonstrated that with the increasing number of MetS parameters there is a proportional raise in the incidence of hypogonadism
increasing number of MetS components is inversely associated with T levels
the presence of MetS did not prove to be a significant determinant of hypogonadism, as it did not lead to a decline in T levels, in MetS patients with already established hypogonadism, the increasing number of MetS features was associated with further decline in T
In the setting of MetS, hypertriglyceridemia and increased WC have been reported as the most important determinants of hypogonadism
recent literature consistently associates obesity not only with higher risk of hypogonadism [4, 6, 27] but also with lower T levels
Visceral adiposity has been particularly related with reduction of T and SHBG levels (independent of other metabolic disorders)
WC was one of the MetS parameters with the greatest influence in T levels decrease, presenting itself as a strong risk factor for hypogonadism development
MetS-related T decline was not accompanied by an increase in pituitary LH levels, suggesting impairment in gonadotropin secretion
The molecules behind this smoothing compensatory effect of GnRH/LH are still unknown, but estrogens and insulin, as well as leptin, TNF-α, and other adipokines, were proposed candidates
fat stores undertake an increase aromatization of androgens, therefore raising estrogen levels [9, 15], which in turn decrease LH secretion
our data contradicts the concept that estradiol exerts a negative feedback on hypothalamic GnRH secretion
taking into account that high estradiol levels have already been described as the only abnormality in a subset of patients with ED, the hypothesis that the later might not only be caused by androgen deficiency is becoming increasingly evident
it has been reported that the chronic exposure to phosphodiesterase type 5 inhibitors (PDE5i), widely used for the treatment of ED, may influence serum estradiol levels
thyroid disorders (specially hyperthyroidism) have been related to ED and hypogonadism, and so must be considered in a sexual-dysfunction setting
It is clear from the current literature that collecting a more thorough hormonal panel might be a wise approach to further uncover hormonal relations
outstanding point. This hits to the point that Low T is the effect not the cause.
We concluded that in ED patients with hypogonadism and MetS, the attenuated response of HPG axis (normal or low LH levels) might not always be due to an underlying adiposity-dependent estrogen-raising effect.
our findings indicate that ED, aging, and estradiol might have a stronger connection than what is currently described in the literature.
this study underlines the importance of the collection of a full hormonal panel in ED men
Energy storage occurs mainly at the level of white adipose tissue, where adipocytes secrete the anorexigenic adipokine leptin
humans and laboratory animals with leptin or insulin deficiency or resistance and/or increased ghrelin levels exhibit delayed or absent puberty and frequently display hypogonadotropic hypogonadism, which prevents fertility
Ghrelin suppresses pulsatile gonadotropin-releasing hormone (GnRH) release [14,15], thus serving as a signal to suppress reproduction in times of famine
Good, although brief, discussion of the interaction between metabolism and hormones. Kisspeptin is a GNRH secreatagogue "upstream". Insulin, Leptin, and Gherlin can inhibit GNRH through resistance and low levels. Probably a U shaped graph of optimal activity.
Study finds that leptin, PAI-1, and hsCRP are positively associated with increasing metabolic syndrome components. Adiponectin was negative associated with increasing MetS. Not a lot of new info here.
Studies have shown that ED may be an early biomarker of general endothelial dysfunction, atherosclerosis and CVD
testosterone treatment of hypogonadal young and older men improves sexual function, increases lean mass and decreases fat mass
In men with low serum testosterone (for example, <8 or 230 nmol l−1) with obesity, metabolic syndrome and diabetes mellitus, treatment with testosterone is warranted
In obese middle-aged men, testosterone treatment reduced visceral adipocity, insulin resistance, serum cholesterol and glucose levels
testosterone replacement has a favorable impact on body mass, insulin secretion and sensitivity, lipid profile and blood pressure in hypogonadal men with the metabolic syndrome as well as type 2 diabetes mellitus
Testosterone significantly inhibits lipoprotein lipase activity, which reduces triglycerides uptake into adipocytes in the abdominal adipose tissue
testosterone treatment decreased endogenous inflammatory cytokines (tumor necrosis factor-α and IL-1β) and lipids (total cholesterol) and increased IL-10 in hypogonadal men
Testosterone treatment reduced leptin and adiponectin levels in hypogonadal type 2 diabetic men after 3 months of testosterone replacement
available data clearly show a relationship between obesity, low testosterone levels and ED
Obesity adversely affects endothelial function and lowers serum testosterone levels through the development of insulin resistance and metabolic syndrome
Metabolic disturbances as well as production of cytokines and adipokines by inflamed fat cells may be causal factors in the development of ED
The onset of ED and the associated risk of CVD may be delayed through lifestyle modifications that affect obesity, such as diet and exercise
Very low testosterone levels contribute to the development of ED in obesity, metabolic syndrome and type 2 diabetes mellitus
Obesity is associated with low total testosterone levels that can be explained at least partially by lower sex hormone-binding globulin (SHBG) in obese men
epidemiological studies have shown a negative correlation between BMI and total testosterone and to a lesser extent with free and bioavailable (biologically active) testosterone levels
defined by consistent symptoms and signs of androgen deficiency, and an unequivocally low serum testosterone level
the threshold serum testosterone level below which adverse clinical outcomes occur in the general population is not known
most population-based studies use the serum testosterone level corresponding to the lower limit, quoted from 8.7 to 12.7 nmol/L, of the normal range for young Caucasian men as the threshold
Researchers tried to examine whether serum total or free testosterone would be a better/more reliable choice when studying the effect of testosterone. The results were mixed. Some reported significant associations of both serum total and free testosterone level with clinical parameters25, whereas others reported that only serum free testosterone26 or only serum total testosterone6 showed significant associations.
−0.124 nmol/L/year in serum total testosterone
this equates to a 4 ng/dl decline annually in total Testosterone.
In experimental studies, androgen receptor knockout mice developed significant insulin resistance rapidly
In mouse models, testosterone promoted differentiation of pluripotent stem cells to the myogenic lineage
testosterone decreased insulin resistance by enhancing catecholamine induced lipolysis in vitro, and reducing lipoprotein lipase activity and triglyceride uptake in human abdominal tissue in vivo
by promoting lipolysis and myogenesis, testosterone might lead to improved insulin resistance
testosterone regulated skeletal muscle genes involved in glucose metabolism that led to decreased systemic insulin resistance
In the liver, hepatic androgen receptor signaling inhibited development of insulin resistance in mice
independent and inverse association of testosterone with hepatic steatosis shown in a cross-sectional study carried out in humans
In short, androgen improves insulin resistance by changing body composition and reducing body fat.
Although a low serum testosterone level could contribute to the development of obesity and type 2 diabetes through changes in body composition, obesity might also alter the metabolism of testosterone
In obese men, the peripheral conversion from testosterone to estrogen could attenuate the amplitude of luteinizing hormone pulses and centrally inhibit testosterone production
leptin, an adipokine, has been shown to be inversely correlated with serum testosterone level in men
Leydig cells expressed leptin receptors and leptin has been shown to inhibit testosterone secretion, suggesting a role of obesity and leptin in the pathogenesis of low testosterone
Baltimore Longitudinal Study of Aging (BLSA) cohort made up of 3,565 middle-class, mostly Caucasian men from the USA, the incidence of low serum total testosterone increased from approximately 20% of men aged over 60 years, 30% over 70 years, to 50% over 80 years-of-age
30–44% sex hormone binding globulin (SHBG)-bound testosterone and 54–68% albumin-bound testosterone
As the binding of testosterone to albumin is non-specific and therefore not tight, the sum of free and albumin-bound testosterone is named bioavailable testosterone, which reflects the hormone available at the cellular level
Serum total testosterone is composed of 0.5–3.0% of free testosterone unbound to plasma proteins
alterations in SHBG concentration might affect total serum testosterone level without altering free or bioavailable testosterone
listed in TableT
A significant, independent and longitudinal effect of age on testosterone has been observed with an average change of −0.124 nmol/L/year in serum total testosterone28. The same trend has been shown in Europe and Australia
Asian men residing in HK and Japan, but not those living in the USA, had 20% higher serum total testosterone than in Caucasians living in the USA, as shown in a large multinational observational prospective cohort of the Osteoporotic Fractures in Men Study
subjects with chronic diseases consistently had a 10–15% lower level compared with age-matched healthy subjects
In Caucasians, the mean serum total testosterone level for men in large epidemiological studies has been reported to range from 15.1 to 16.6 nmol/L
Asians, higher values, ranging from 18.1 to 19.1 nmol/L, were seen in Korea and Japan
Chinese middle-aged men reported a similar mean serum testosterone level of 17.1 nmol/L in 179 men who had a family history of type 2 diabetes and 17.8 nmol/L in 128 men who had no family history of type 2 diabetes
The reduction of total testosterone was 0.4% per year in both groups
HK involving a cohort of 1,489 community-dwelling men with a mean age of 72 years, a mean serum total testosterone of 19.0 nmol/L was reported
pro-inflammatory factors, such as tumor necrosis factor-α in the testes, could locally inhibit testosterone biosynthesis in Leydig cells47, and testosterone treatment in men was shown to reduce the level of tumor necrosis factor-α
In Asians, a genetic deletion polymorphism of uridine diphosphate-glucuronosyltransferase UGT2B17 was associated with reduced androgen glucuronidation. This resulted in higher level of active androgen in Asians as compared to Caucasians, as Caucasians' androgen would be glucuronidated into inactive forms faster.
Compared with Caucasians, the frequency of this deletion polymorphism of UGT2B17 was 22-fold higher in Asian subjects
Other researchers have suggested that environmental, but not genetic, factors influenced serum total testosterone
The basal and ligand-induced activity of the AR is inversely associated with the length of the CAG repeat chain
In the European Male Aging Study, increased estrogen/androgen ratio in association with longer AR CAG repeat was observed
a smaller number of AR CAG repeat had been shown to be associated with benign prostate hypertrophy and faster prostate growth during testosterone treatment
In India, men with CAG ≤19 had increased risk of prostate cancer
the odds of having a short CAG repeat (≤17) were substantially higher in patients with lymph node-positive prostate cancer than in those with lymph node-negative disease or in the general population
assessing the polymorphism at the AR level could be a potential tool towards individualized assessment and treatment of hypogonadism.
In elderly men, there was reduced testicular response to gonadotropins with suppressed and altered pulsatility of the hypothalamic pulse generator
a significant, independent and longitudinal effect of age on serum total testosterone level had been observed
A significant graded inverse association between serum testosterone level and insulin levels independent of age has also been reported in Caucasian men
Low testosterone is commonly associated with a high prevalence of MES
most studies showed that changes in serum testosterone level led to changes in body composition, insulin resistance and the presence of MES, the reverse might also be possible
MES predicted a 2.6-fold increased risk of development of low serum testosterone level independent of age, smoking and other potential confounders
Other prospective studies have shown that development of MES accelerated the age-related decline in serum testosterone level
In men with type 2 diabetes, changes in serum testosterone level over time correlated inversely with changes in insulin resistance
weight loss by either diet control or bariatric surgery led to a substantial increase in total testosterone, especially in morbidly obese men, and the rise in serum testosterone level was proportional to the amount of weight lost
To date, published clinical trials are small, of short duration and often used pharmacological, not physiological, doses of testosterone
In the population-based Osteoporotic Fractures in Men Study cohort from Sweden, men in the highest quartile of serum testosterone level had the lowest risk of cardiovascular events compared with men in the other three quartiles (hazard ratio [HR] 0.70
low serum total testosterone was associated with a significant fourfold higher risk of cardiovascular events when comparing men from the lowest testosterone tertile with those in the highest tertile
Shores et al. were the first to report that low serum testosterone level, including both serum total and free testosterone, was associated with increased mortality
low serum total testosterone predicted increased risk of cardiovascular mortality with a HR of 1.38
low serum total testosterone increased all-cause (HR 1.35, 95% CI 1.13–1.62, P < 0.001) and cardiovascular mortality (HR 1.25
European Association for the Study of Diabetes 2013 suggested there was an inverse relationship between serum testosterone level and acute myocardial infarction
Diabetic men in the highest quartile of serum total testosterone had a significantly reduced risk of acute MI when compared with those in the lower quartiles
serum total testosterone level in the middle two quartiles at baseline predicted reduced incidence of death compared with having the highest and lowest levels
Nice review of Testosterone levels and some of the evidence linking Diabetes with low T. However, the conclusion by the authors regarding what is causing the low T in men with Diabetes is baffling. The literature does not point to one cause, it is clearly multifactorial--obesity, inflammation, high aromatase activity...I would suggest the authors continue their readings in the manner.
Berberine reduced BMI, improved insulin sensitivity, improved leptin sensitivity, and improved leptin:adiponectin ratio levels in people with metabolic syndrome after 3 months.