Significant Increase In Adiposity Research Articles

Perinatal triphenyl phosphate exposure induces metabolic dysfunctions through the EGFR/ERK/AKT signaling pathway: Mechanistic in vitro and in vivo studies

Triphenyl phosphate (TPhP), a widely used organophosphate-flame retardant, is ubiquitously found in household environments and may adversely affect human health. Evidence indicates that TPhP exposure causes metabolic dysfunctions in vivo; however, the underlying mechanism of such adverse effects has not been comprehensively investigated. Herein, we utilized two in vitro models including mouse and human preadipocytes to delineate adipogenic mechanisms of TPhP. The results revealed that both mouse and human preadipocytes exposed to TPhP concentration-dependently accumulated more fat through a significant upregulation of epidermal growth factor receptor (EGFR). We demonstrated that TPhP significantly promoted adipogenesis through the activation of EGFR/ERK/AKT signaling pathway as evident by a drastic reduction in adipogenesis of preadipocytes cotreated with inhibitors of EGFR and its major effectors. Furthermore, we confirmed the mechanism of TPhP-induced metabolic dysfunctions in vivo. We observed that male mice perinatally exposed to TPhP had a significant increase in adiposity, hepatic triglycerides, insulin resistance, plasma insulin levels, hypotension, and phosphorylated EGFR in gonadal fat. Interestingly, an administration of a potent and selective EGFR inhibitor significantly ameliorated the adverse metabolic effects caused by TPhP. Our findings uncovered a potential mechanism of TPhP-induced metabolic dysfunctions and provided implications on toxic metabolic effects posed by environmental chemicals.

Glucose intolerance develops prior to increased adiposity and accelerated cessation of estrous cyclicity in female growth-restricted rats.

BackgroundThe incidence of metabolic disease increases in early menopause. Low birth weight influences the age at menopause. Thus, this study tested the hypothesis that intrauterine growth restriction programs early reproductive aging and impaired glucose homeostasis in female rats.MethodsEstrous cyclicity, body composition, and glucose homeostasis were determined in female control and growth-restricted rats at 6 and 12 months of age; sex steroids at 12 months.ResultsGlucose intolerance was present at 6 months of age prior to cessation of estrous cyclicity and increased adiposity in female growth-restricted rats. However, female growth-restricted rats exhibited persistent estrus and a significant increase in adiposity, fasting glucose and testosterone at 12 months of age (P<0.05). Insulin release in response to a glucose challenge was blunted in conjunction with a reduction in protein expression of pancreatic glucose transporter type 2 and estrogen receptor alpha at 12 months of age in female growth-restricted rats (P<0.05).ConclusionThis study demonstrated that slow fetal growth programmed glucose intolerance that developed prior to early estrous acyclicity; yet, fasting glucose levels were elevated in conjunction with increased adiposity, accelerated cessation of estrous cyclicity and a shift towards testosterone excess at 12 months of age in female growth-restricted rats.

Impact of Commercial Vendor on The Developmental Programming of Later Chronic Health

Low birth weight is associated with increased risk of metabolic disease including hypertension in later life. Reduced uterine perfusion (RUP) in timed pregnant SD rats purchased from Harlan induces intrauterine growth restriction (IUGR) associated with the development of glucose intolerance, increased adiposity, and hypertension in female IUGR offspring by 12 months of age. Whether the commercial source of the SD rat impacts the programming of chronic health is unknown. Thus, the aim of this study was to investigate whether the commercial vendor altered adult outcome following a developmental insult. Timed pregnant SD rats were purchased from Harlan (H) or Charles River (CR) and subjected to RUP or sham surgery at day 14 of gestation. Control and IUGR offspring were studied at 1 year of age. RUP decreased birth weight in H and CR pups (P<0.05). However, by 12 months of age offspring from CR exhibited a significant increase in adiposity (P<0.05) regardless of fetal health that abolished the impact of IUGR. Thus, these studies indicate the same strain provided by different vendors greatly impacts the fetal programming of chronic health. NIH:HL074927, HL51971, P20GM104357, AHA GRNT19900004 Control (H) IUGR (H) Control (CR) IUGR (CR) Fat Mass (g) 27.4±2.6 38.7±4.3* 93.8±13.7*† 90.2±15.2*† MAP (mmHg) 119.4±3.0 136.8±2.4* 129.9±4.0* 130.9±3.2* AUG OGTT 479.5±42.7 714.2±27.8* 563.8±38.1† 511.4±24.2† * P < 0.05 vs. Control H; † P < 0.05 vs. IUGR H

The Decline in Pulsatile GH Secretion throughout Early Adulthood in Mice Is Exacerbated by Dietary-Induced Weight Gain

The transition between puberty and adulthood is accompanied by a slowing in linear growth. Although GH is a key factor that drives somatic development into adulthood, early adulthood coincides with a reduction in circulating levels of GH. To this extent, a pathological decline in postpubertal GH secretion is detrimental to attainment of peak lean muscle mass and bone mass and promotes adiposity and increases susceptibility to the development of obesity in adulthood. Here we characterized pulsatile GH secretion in C57BL/6J mice at 12 and 16 wk of age. Deconvolution analysis of these measures reveals a reduction in pulsatile GH secretion between 12 and 16 wk of age. Dietary intervention with high-fat feeding at 8 wk of age results in a significant increase in adiposity, the development of glucose intolerance, and hyperinsulinemia. We show the exacerbation of the age-associated decline in pulsatile GH secretion in high-fat-fed mice after 4 wk of dietary intervention (at 12 wk of age), and a further suppression of pulsatile GH secretion by 8 wk of dietary intervention (at 16 wk of age). Suppressed pulsatile secretion of GH did not coincide with an elevation in circulating free fatty acids. Rather, we observed increased hepatic triglyceride content and an eventual decrease in circulating levels of IGF-I. Given the established role of GH in maintaining healthy aging, we anticipate that an advancing of the age-associated decline in pulsatile GH secretion as a consequence of dietary-induced weight gain may have long-term ramifications on adult health.

Principles of strategic drug delivery to the brain (SDDB): Development of anorectic and orexigenic analogs of leptin

The blood–brain barrier (BBB) presents a tremendous challenge for the delivery of drugs to the central nervous system (CNS). This includes drugs that target brain receptors for the treatment of obesity and anorexia. Strategic drug delivery to brain (SDDB) is an approach that considers in depth the relations among the BBB, the candidate therapeutic, the CNS target, and the disease state to be treated. Here, we illustrate principles of SDDB with two different approaches to developing drugs based on leptin. In normal body weight humans and in non-obese rodents, leptin is readily transported across the BBB and into the CNS where it inhibits feeding and enhances thermogenesis. However, in obesity, the transport of leptin across the BBB is impaired, resulting in a resistance to leptin. As a result, it is difficult to treat obesity with leptin or its analogs that depend on the leptin transporter for access to the CNS. To treat obesity, we developed a leptin agonist modified by the addition of pluronic block copolymers (P85-leptin). P85-leptin retains biological activity and is capable of crossing the BBB by a mechanism that is not dependent on the leptin transporter. As such, P85-leptin is able to cross the BBB of obese mice at a rate similar to that of native leptin in lean mice. To treat anorexia, we developed a leptin antagonist modified by pegylation (PEG-MLA) that acts primarily by blocking the BBB transporter for endogenous, circulating leptin. This prevents blood-borne, endogenous leptin from entering the CNS, essentially mimicking the leptin resistance seen in obesity, and resulting in a significant increase in adiposity. These examples illustrate two strategies in which an understanding of the interactions among the BBB, CNS targets, and candidate therapeutics under physiologic and diseased conditions can be used to develop drugs effective for the treatment of brain disease.

Your brain on fat: dietary-induced obesity impairs central nutrient sensing

the past decade has witnessed a rejuvenated interest in the ability of the central nervous system (CNS) to sense and respond to changes in nutrient availability. This interest has been driven in part by a conceptual framework where the CNS receives signals regarding nutrient availability that are

Determinants of Adiposity during Preweaning Postnatal Growth in Appropriately Grown and Growth-Restricted Term Infants

The distribution and quantity of adipose tissue are markers of morbidity risk in children and adults. Poor intrauterine growth and accelerated postnatal growth are believed to add to these risks. The aim of this study was to assess adipose tissue content and distribution at birth and 6 wk in relation to intrauterine growth restriction, postnatal growth, and infant diet. We measured weight, length, and head circumference and adipose content and distribution using magnetic resonance imaging at 6 wk of age in appropriately grown for gestational age (AGA) and growth-restricted (GR) infants and compared this with birth data. By 6 wk, GR infants showed complete catch-up in comparison to AGA infants in relation to head growth and adiposity. Catch-up in length and weight was not complete. Accelerated linear growth, but not accelerated weight gain, was associated with a highly significant increase in adiposity (r = 0.57, p = 0.001) regardless of AGA/GR status. The highest adiposity at 6 wk, allowing for baseline variables and linear growth, was seen in exclusively breast-fed GR infants (mean, 95% confidence interval: 33.5%, 29.51-37.5). Adipose tissue distribution remained constant and was unrelated to growth and diet. Reduced birth adiposity (B = -0.185, p = 0.003), but not low birth head size (B = 0.32, p = 0.093), was a significant predictor of accelerated postnatal head growth (R(2) = 0.29, adjusted R(2) = 0.23, p = 0.012). Increasing adiposity appears to be an inevitable accompaniment of accelerated linear growth. Low total adipose tissue quantity at birth appears to direct nutrition toward head growth. Adipose tissue may be involved in the signaling of catch-up growth.

Long term treatment with olanzapine mixed with the food in male rats induces body fat deposition with no increase in body weight and no thermogenic alteration

Body weight gain is a worrying side effect of many new antipsychotic drugs. The mechanisms by which antipsychotic drugs increase weight in humans are not known. Attempts to model the metabolic effects of antipsychotic drugs in the animal have not been successful. Female rats appear to be sensitive to the effects of antipsychotics, but male rats less, and this does not match the clinical situation in humans. In previous rodent studies, antipsychotics were always given by daily gavage or injections. Antipsychotics have different pharmacokinetics in rodents and humans, and in the present study, we tested the hypothesis that the insensitivity of male rats to the effects of antipsychotics could be related to their mode of administration. Thus, we administered antipsychotic drugs mixed with the food. Animals were treated during 6 weeks with haloperidol (1 mg/kg), olanzapine (1 mg/kg), ziprasidone (10 mg/kg), or a control solution. Animals were allowed to self-select food among three macronutrients (carbohydrates, lipids and proteins). Food selection was measured throughout the study. At the end of the study, body composition was measured by dissection and weighing of the rat's main organs and tissues. Mitochondrial thermogenesis was measured in brown adipose tissue in olanzapine-treated animals. Circulating leptin, insulin, glucose, triglycerides, cholesterol, high-density lipoprotein (HDL) were also assayed at the end of the study. The results show that none of the antipsychotic treatments modified caloric intake, food selection or body weight. Olanzapine did not alter mitochondrial thermogenesis. However, haloperidol and olanzapine induced a significant increase in adiposity and circulating leptin. Ziprasidone produced a moderate fat accumulation. It is concluded that mixing antipsychotic treatments with the food provides a reliable animal model of antipsychotic-induced fat accumulation.

IN FOCUS: Pioglitazone protects against thrombosis in a mouse model of obesity and insulin resistance

As arterial thrombosis accounts for the vast majority of cardiovascular complications in obese, insulin resistant patients, we hypothesized that improving insulin sensitivity may be effective in reducing the thrombotic response following vascular injury. We investigated the effect of the thiazolidinedione drug, pioglitazone, on the thrombotic response to injury in obese, insulin resistant mice. Insulin-resistant, obesity-prone mice (KK strain) were treated with pioglitazone, placebo, or the sulfonylurea compound, glipizide, for 2.5 weeks and then subjected to photochemical injury of the carotid artery. KK mice have a significant increase in adiposity (7 weeks: 25.6%; 15 weeks: 34.4%; P < 0.0001) and thrombotic tendency (7 weeks: 21.2 +/- 1.9 min; 15 weeks: 13.7 +/- 1.7 min; P < 0.01) with age. Pioglitazone provided significant protection from thrombosis at both time points, prolonging the time to occlusive thrombosis by 40% and 68%, at 7 and 15 weeks of age, respectively (P < 0.05). Similarly, following a diet-challenge to promote diabetes, pioglitazone provided protection from occlusive thrombus formation (Placebo: 11.3 +/- 1.0 min; Pioglitazone: 22.3 +/- 3.9 min; P < 0.05). However, despite a salient effect of glipizide on the hyperglycemia of the mice, there was no effect on the time to occlusive thrombus formation (13.2 +/- 0.9 min, n = 4) compared with placebo-treated mice. The pioglitazone protection was paralleled by significantly lower soluble P-selectin and platelet P-selectin expression providing evidence of an antiplatelet effect. We conclude that pioglitazone treatment provides protection against arterial thrombosis in an obese, insulin resistant, prothrombotic mouse model.

Low plasma leptin in response to dietary fat in diabetes- and obesity-prone mice.

Despite the fact that mutations resulting in the absence of leptin or its receptor have been associated with severe obesity and diabetes, such mutations do not appear to be responsible for most human obesity. Indeed, diet-induced obesity in animals and humans has been characterized by hyperleptinemia. This has been interpreted as evidence for leptin resistance. However, no careful longitudinal studies evaluating the role of leptin in the development of obesity exist. We report a series of studies in A/J and C57BL/6J (B/6) mice that demonstrate a direct relationship between the ability to increase plasma leptin levels in response to a high-fat diet and resistance to the subsequent development of obesity and diabetes. While leptin levels are similar in lean, low-fat-fed A/J and B/6 mice, the effects of a high-fat diet on plasma leptin differ dramatically between the two strains. After 4 weeks of high-fat feeding, leptin levels in A/J mice increased 10-fold, and this elevated level was maintained independent of weight gain throughout a 14-week feeding period. However, in B/6 mice, leptin levels remained at least twofold lower and only rose very gradually along with a significant increase in adiposity, hyperglycemia, and hyperinsulinemia. These differences in the response of leptin to diet are independent of food intake and plasma insulin levels during the 1st month of feeding. Further, we demonstrated that leptin administration did not influence the expression of the novel uncoupling protein UCP2, which also responds to dietary fat. From these results, we suggest that the response of leptin to fat feeding may be an important predictor of the development of subsequent obesity.

Brown fat thermogenesis and its role in the development of obesity

The role of brown fat thermogenesis in the development of obesity is considered from a number of perspectives. In adult rats, the impact of scapular brown fat lipectomy on carcass fat accretion was examined in three different rodent models: the Zucker lean (Fa/−) rat which is relatively resistant to obesity, the Zucker obese (fa/fa) rat which is characterized by a particularly severe form of hyperplastic obesity and the Osborne Mendel rat which remains lean on a standard pelleted diet but readily becomes obese on a palatable high fat diet. The consequences of brown fat lipectomy varied from no effect on carcass white fat accretion in Zucker Fa/− lean rats to a significant increase in adiposity in the Zucker fatty fa/fa relative to their respective sham-operated controls. The effect of the Osborne Mendel rat was intermediate between the Fa/− and the fa/fa. The results point to the importance of genetic background with respect to the impact of brown fat lipectomy on the development of white fat adiposity. In the developing Zucker rat at 2 and 8 days of age, in vivo evidence is presented to support the concept that brown fat thermogenesis is attenuated in the fatty fa/fa preobese pup. In animals of the fatty fa/fa genotype, maximum oxygen consumption in response to acute cold exposure was lower than in lean pups of the Fa/Fa genotype. Moreover, at 8 days of age, the rectal temperature of the cold-exposed fa/fa pups fell more precipitously than did that of the lean during the period of cold exposure. The genetic obesity of the fatty fa/fa rat at 8 days of age was contrasted with that of 8-day old Zucker genetically lean Fa/Fa pups raised in small litters, a manipulation that results in a type of dietary obesity. The rate of oxygen consumption in response to cold was significantly increased in the overfed pups as compared to both genetically obese (fa/fa) pups and genetically lean (Fa/Fa) pups raised in normal sized litters. Our data support the concept that although the obesity of the fatty fa/fa rat pup was associated with a failure of brown fat mediated thermogenesis, there appeared to be no such failure in the overfed Fa/Fa lean pups during the initial phase of overfeeding.