Elevated FFA concentrations have been shown to reproduce some of the metabolic abnormalities of obesity. It has been hypothesized that visceral adipose tissue lipolysis releases excess FFAs into the portal vein, exposing the liver to higher FFA concentrations. We used isotope dilution/hepatic vein catheterization techniques to examine whether intra-abdominal fat contributes a greater portion of hepatic FFA delivery in visceral obesity. Obese women (n = 24) and men (n = 20) with a range of obesity phenotypes, taken together with healthy, lean women (n = 12) and men (n = 12), were studied. Systemic, splanchnic, and leg FFA kinetics were measured. The results showed that plasma FFA concentrations were approximately 20% greater in obese men and obese women. The contribution of splanchnic lipolysis to hepatic FFA delivery ranged from less than 10% to almost 50% and increased as a function of visceral fat in women (r = 0.49, P = 0.002) and in men (r = 0.52, P = 0.002); the slope of the relationship was greater in women than in men (P < 0.05). Leg and splanchnic tissues contributed a greater portion of systemic FFA release in obese men and women than in lean men and women. We conclude that the contribution of visceral adipose tissue lipolysis to hepatic FFA delivery increases with increasing visceral fat in humans and that this effect is greater in women than in men. IntroductionA predominantly upper-body fat distribution is an important risk factor for the metabolic complications of obesity (1), especially when it is associated with increased intra-abdominal fat (2). Several metabolic abnormalities associated with upper-body obesity can be reproduced by excess FFAs, including insulin resistance with respect to muscle glucose uptake (3) and endogenous glucose production (4) and increased VLDL triglyceride production (5). Increased delivery of FFAs to the liver may be responsible for some of these abnormalities (6, 7). Visceral adipocytes are more lipolytically active than subcutaneous adipocytes in vitro (8, 9), suggesting that the association between greater amounts of visceral fat and the metabolic complications of obesity may reflect excess FFAs originating from visceral adipose tissue lipolysis (6, 7). These FFAs are released directly into the portal vein, exposing the liver to more FFAs than would be predicted from systemic FFA availability data. Thus, enlarged visceral fat stores could increase the proportion of hepatic FFA delivery coming from visceral, as opposed to systemic, sources.The relationship between visceral fat and splanchnic FFA kinetics has not been assessed in humans. We previously reported a slight, but nonsignificant increase in splanchnic FFA (palmitate) release in upper-body obese women compared with lower-body obese and nonobese women (10). Visceral fat was not measured, however, and we did not include women with the full range of obesity-related metabolic abnormalities (10) in whom more significant disturbances of FFA metabolism might be expected. In addition, men were not studied, and obese ...

We investigated whether previously reported muscle mitochondrial dysfunction and altered gene transcript levels in type 2 diabetes might be secondary to abnormal blood glucose and insulin levels rather than an intrinsic defect of type 2 diabetes. A total of 13 type 2 diabetic and 17 nondiabetic subjects were studied on two separate occasions while maintaining similar insulin and glucose levels in both groups by 7-h infusions of somatostatin, low-or high-dose insulin (0.25 and 1.5 mU/kg of fat-free mass per min, respectively), and glucose. Muscle mitochondrial DNA abundance was not different between type 2 diabetic and nondiabetic subjects at both insulin levels, but the majority of transcripts in muscle that are involved mitochondrial functions were expressed at lower levels in type 2 diabetes at low levels of insulin. However, several gene transcripts that are specifically involved in the electron transport chain were expressed at higher levels in type 2 diabetic patients. After the low-dose insulin infusion, which achieved postabsorptive insulin levels, the muscle mitochondrial ATP production rate (MAPR) was not different between type 2 diabetic and nondiabetic subjects. However, increasing insulin to postprandial levels increased the MAPR in nondiabetic subjects but not in type 2 diabetic patients. The lack of MAPR increment in response to high-dose insulin in type 2 diabetic patients occurred in association with reduced glucose disposal and expression of peroxisome proliferator-activated receptor-␥ coactivator 1␣, citrate synthase, and cytochrome c oxidase I. In conclusion, the current data supports that muscle mitochondrial dysfunction in type 2 diabetes is not an intrinsic defect, but instead a functional defect related to impaired response to insulin. Diabetes 55:3309 -3319, 2006

Primary aldosteronism (PA) affects ~5–10% of hypertensive patients and has unilateral and bilateral forms. Most unilateral PA is caused by computed tomography (CT)-detectable aldosterone-producing adenomas (APA), which express CYP11B2 (aldosterone synthase) and frequently harbor somatic mutations in aldosterone-regulating genes. The etiology of the most common bilateral form of PA, idiopathic hyperaldosteronism (IHA), is believed to be diffuse hyperplasia of aldosterone-producing cells within the adrenal cortex. Herein, a multi-institution cohort of fifteen IHA adrenals were examined with CYP11B2 immunohistochemistry and next generation sequencing (NGS). CYP11B2 immunoreactivity in adrenal glomerulosa harboring non-nodular hyperplasia was only observed in 4/15 IHA adrenals suggesting that hyperplasia of CYP11B2 expressing cells may not be the major cause of IHA. However, the adrenal cortex of all IHA adrenals harbored at least one CYP11B2-positive aldosterone-producing cell cluster (APCC) or a micro-APA. The number of APCCs per case (and individual APCC area) in IHA adrenals was significantly larger than in normotensive controls. NGS of DNA from 99 IHA APCCs demonstrated somatic mutations in genes encoding the L-type calcium voltage-gated channel subunit alpha 1-D (CACNA1D, n=57; 58%) and potassium voltage-gated channel subfamily J-5 (KCNJ5, n=1; 1%). These data suggest that IHA may result from not only hyperplasia, but also the accumulation or enlargement of CT-undetectable APCC harboring somatic aldosterone-driver gene mutations. The high prevalence of mutations in the CACNA1D L-type calcium channel provides a potential actionable therapeutic target that could complement mineralocorticoid blockade and inhibit aldosterone overproduction in some IHA patients.

IntroductionApproximately 50% of postabsorptive energy needs in humans are supplied from the oxidation of fatty acids. The major source of this lipid fuel is circulating FFAs that are released from lipolysis of adipose tissue triglyceride. Maintaining normal FFA availability is of considerable importance in human health (1), because high FFA concentrations are associated with a number of cardiovascular risk factors (2) and a predisposition to type 2 diabetes mellitus (3). Experimentally increasing FFA concentrations in normal humans can induce insulin resistance (4), disordered lipoprotein metabolism (5), altered vascular reactivity (6), and abnormal insulin secretion (7).At rest, an average adult with 15 kg of body fat (>50 moles of fatty acids) releases less than 0.4 mmol/min into the circulation to provide energy for fat-free tissue. This is in striking contrast to glucose fuel, where hepatic glycogen stores are approximately 370 mmol and glucose is released at rates of approximately 0.8 mmol/min (8). Understanding the regulation of this relatively massive adipose tissue fuel depot is important given the prevalence of obesity is increasing rapidly in many Western societies.The factors that regulate changes in FFA release in response to changing lipid fuel needs are relatively well described. The insulin secretion stimulated by carbohydrate ingestion markedly inhibits FFA release, thereby suppressing FFA concentrations and fatty acid oxidation by 80-90% (9). In contrast, carbohydrate deprivation or fasting reduces insulin secretion, which enhances adipose tissue FFA release, allowing FFA concentrations to increase by approximately 300% to facilitate greater fat oxidation. Exercise, the most potent physiological stimulus to fat oxidation, can increase FFA release by more than 300% (10), primarily through increased catecholamine stimulation of adipose β-adrenergic receptors. This relatively good understanding of the short-term regulators of FFA release is not mirrored by an equal appreciation of the factors that influence average resting FFA availability.Understanding the normal interaction between adipose tissue fuel release rates and fat-free mass (FFM) fuel use rates is important for understanding the effects of body fat on health. The approach to comparing fuel release rates between groups with different weights and/or different body composition can influence how the information is interpreted, however. For example, there has been controversy regarding whether obesity causes higher FFA concentrations because of greater release or lesser clearance of FFA from the circulation. Obese adults have FFA release rates similar to lean adults, relative to body weight or body fat (11, 12), Adipose tissue lipolysis supplies circulating FFAs, which largely meet lipid fuel needs; however, excess FFAs, can contribute to the adverse health consequences of obesity. Because "normal" FFA release has not been well defined, average (mean of 4 days) basal FFA release and its potential regulation factors were measured in 50 lean a...

The utilization of blood glycerol and glucose as precursors for intramuscular triglyceride synthesis was examined in rats using an intravenous infusion of [2-14 C]glycerol and [6-3 H]glucose or [6-14 C]glucose. In 24-h fasted rats, more glycerol than glucose was incorporated into intramuscular triglyceride glycerol in soleus (69 ؎ 23 versus 4 ؎ 1 nmol/mol triglyceride/h, respectively, p ‫؍‬ 0.02 glycerol versus glucose) and in gastrocnemius (25 ؎ 5 versus 9 ؎ 2 nmol/mol triglyceride/h, respectively, p ‫؍‬ 0.02). Blood glucose was utilized more than blood glycerol for triglyceride glycerol synthesis in quadriceps. In fed rats, the blood glycerol incorporation rates (4 ؎ 2, 8 ؎ 3, and 9 ؎ 3 nmol/mol triglyceride/h) were similar (p > 0.3) to those of glucose (5 ؎ 2, 8 ؎ 2, and 5 ؎ 2 nmol/mol triglyceride/h for quadriceps, gastrocnemius, and soleus muscle, respectively). Glucose incorporation into intramuscular triglycerides was less with [6- 13 C]glycerol) was complete in quadriceps and gastrocnemius, but not soleus, within 2 h after beginning the tracer infusion. We conclude that blood glycerol is a direct and important precursor for muscle triglyceride synthesis in rats, confirming the presence of functionally important amounts of glycerol kinase in skeletal muscle.It is a biochemistry precept that the glycerol moiety of triacylglycerols and phospholipids in non-hepatic mammalian tissues is primarily derived from glucose via glycolysis (1). Dihydroxyacetone phosphate (DHAP), 1 originating from glucose, is reduced to glycerol 3-phosphate (G3P) by the action of glycerophosphate dehydrogenase. G3P then undergoes sequential acylation steps to incorporate three fatty acids to form a triacylglycerol (TG) (2). DHAP can also take a different path (DHAP pathway) via 1-acyldihydroxyacetone phosphate and then 1-acylglycerol 3-phosphate, but this appears to be a quantitatively minor reaction (3, 4). Glycerol can be converted directly to G3P by glycerol kinase, but this is believed to occur primarily, if not solely, in the liver and kidney because the glycerol kinase activity in these tissues is sufficient to permit large quantities of blood glycerol to be used for gluconeogenesis and TG synthesis. The direct conversion of free glycerol to G3P is thought to be negligible in skeletal muscle and adipose tissue because of their low activities of glycerol kinase (5-8). A corollary to this supposition is that glycerol generated by the hydrolysis of TG in skeletal muscle quantitatively enters the circulation. These assumptions form the basis for using systemic glycerol appearance rate, measured by isotope dilution techniques, as a quantitative measure of whole body lipolysis (9, 10).The presence of small but measurable glycerol kinase activity in skeletal muscle of various animal species, including rat (5) and humans (6), raises concerns as to the validity of these assumptions, however. For example, although low in specific activity, skeletal muscle glycerol kinase could be important in the metabolism of circulating glycerol consid...

An experimental study is conducted on localized bulging of inflated latex rubber tubes of a range of wall thicknesses and tube lengths, guided by newly emerged analytical results. In the case when the tube has one free closed end that may or may not be subjected to a dead weight, the initiation pressure for localized bulging is determined by a bifurcation condition, and the propagation pressure is determined by Maxwell's equal-area rule. It is shown that after bulge initiation the pressure will decrease monotonically towards, but will never reach, the propagation pressure, and it is when the pressure is sufficiently close to this propagation pressure that rapid propagation of the bulge in the axial direction takes place. It is found that the experimentally observed initiation pressure is around 15% below the theoretical prediction, which is consistent with the fact that bulging initiation is a subcritical phenomenon and is therefore sensitive to imperfections. The experimentally observed propagation pressure is always very close to the theoretical prediction, which confirms the insensitivity of this pressure to imperfections and demonstrates the predictive power of the material model fitted from our own experiments on equibiaxial stretching. In the other case when the tube is first stretched and then fixed at both ends, bulge initiation takes place in the same manner as in the previous case, but the propagation pressure is no longer determined by Maxwell's equal-area rule. After bulge initiation the pressure will first decrease to a minimum and then rises slowly, and it is on the latter ascending path that the bulge starts to propagate rapidly in the axial direction. A semi-analytical method is proposed for the determination of the minimum pressure. Numerical simulations with the use of the software Abaqus are also conducted to verify the theoretical predictions.

SSST is highly sensitive and superior to RSST in identifying both unilateral and bilateral forms of PA and has a low rate of false positives and inconclusive results. It therefore offers a reliable and much less complicated and expensive alternative to FST for confirming PA.

Species of Fusarium have significant agro-economical and human health-related impact by infecting diverse crop plants and synthesizing diverse mycotoxins. Here, we investigated interactions of grain-feeding Tenebrio molitor larvae with four grain-colonizing Fusarium species on wheat kernels. Since numerous metabolites produced by Fusarium spp. are toxic to insects, we tested the hypothesis that the insect senses and avoids Fusarium-colonized grains. We found that only kernels colonized with F. avenaceum or Beauveria bassiana (an insect-pathogenic fungal control) were avoided by the larvae as expected. Kernels colonized with F. proliferatum, F. poae or F. culmorum attracted T. molitor larvae significantly more than control kernels. The avoidance/preference correlated with larval feeding behaviors and weight gain. Interestingly, larvae that had consumed F. proliferatum- or F. poae-colonized kernels had similar survival rates as control. Larvae fed on F. culmorum-, F. avenaceum- or B. bassiana-colonized kernels had elevated mortality rates. HPLC analyses confirmed the following mycotoxins produced by the fungal strains on the kernels: fumonisins, enniatins and beauvericin by F. proliferatum, enniatins and beauvericin by F. poae, enniatins by F. avenaceum, and deoxynivalenol and zearalenone by F. culmorum. Our results indicate that T. molitor larvae have the ability to sense potential survival threats of kernels colonized with F. avenaceum or B. bassiana, but not with F. culmorum. Volatiles potentially along with gustatory cues produced by these fungi may represent survival threat signals for the larvae resulting in their avoidance. Although F. proliferatum or F. poae produced fumonisins, enniatins and beauvericin during kernel colonization, the larvae were able to use those kernels as diet without exhibiting increased mortality. Consumption of F. avenaceum-colonized kernels, however, increased larval mortality; these kernels had higher enniatin levels than F. proliferatum or F. poae-colonized ones suggesting that T. molitor can tolerate or metabolize those toxins.