Pituitary adenylate cyclase-activating polypeptide (PACAP) is a widely distributed neuropeptide that acts as a neurotransmitter, neuromodulator, neurotropic factor, neuroprotectant, secretagogue, and neurohormone. Owing to its pleiotropic biological actions, knockout of Pacap (Adcyap1) has been shown to induce several abnormalities in mice such as impaired thermoregulation. However, the underlying physiological and molecular mechanisms remain unclear. A previous report has shown that cold-exposed Pacap null mice cannot supply appropriate levels of norepinephrine (NE) to brown adipocytes. Therefore, we hypothesized that exogenous NE would rescue the impaired thermogenic response of Pacap null mice during cold exposure. We compared the adaptive thermogenic capacity of Pacap K/K to Pacap C/C mice in response to NE when housed at room temperature (24 8C) and after a 3.5-week cold exposure (4 8C). Biochemical parameters, expression of thermogenic genes, and morphological properties of brown adipose tissue (BAT) and white adipose tissue (WAT) were also characterized. Results showed that there was a significant effect of temperature, but no effect of genotype, on the resting metabolic rate in conscious, unrestrained mice. However, the normal cold-induced increase in the basal metabolic rate and NE-induced increase in thermogenesis were severely blunted in cold-exposed Pacap K/K mice. These changes were associated with altered substrate utilization, reduced b 3 -adrenergic receptor (b 3 -Ar (Adrb3)) and hormone-sensitive lipase (Hsl (Lipe)) gene expression, and increased fibroblast growth factor 2 (Fgf2) gene expression in BAT. Interestingly, Pacap K/K mice had depleted WAT depots, associated with upregulated uncoupling protein 1 expression in inguinal WATs. These results suggest that the impairment of adaptive thermogenesis in Pacap null mice cannot be rescued by exogenous NE perhaps in part due to decreased b 3 -Ar-mediated BAT activation.

The adaptive hypothesis that an obese-prone genotype confers a fitness advantage when challenged with food restriction and food-related locomotion was tested using a rat model. Juvenile (35-40 days) and adolescent (45-50 days) JCR:LA-cp rats, obese prone (cp/cp) and lean prone ( þ /?), were exposed to 1.5 h daily meals and 22.5 h of voluntary wheel running, a procedure that normally leads to self-starvation. Genotype had a dramatic effect on survival of rats when exposed to the challenge of food restriction and wheel running. Although similar in initial body weight, obese-prone juveniles survived twice as long, and ran three times as far, as their lean-prone counterparts. Biochemical measures indicated that young obese-prone animals maintained blood glucose and fat mass, whereas lean-prone rats depleted these energy reserves. Corticosterone concentration indicated that obese-prone juveniles exhibited a lower stress response to the survival challenge than lean-prone rats, possibly due to lower energy demands and greater energy reserves. Collectively, the findings support the hypothesis that an obese-prone genotype provides a fitness advantage when food supply is inadequate, but is deleterious during periods of food surfeit, such as the energy-rich food environment of prosperous and developing societies worldwide. Keywords: adaptation; food restriction; wheel running; genotype; survival Obesity is portrayed as a weight disorder with negative connotations of susceptibility to diabetes, 1 the metabolic syndrome, 2 heart disease 3 and cancer(s). 4 The modern clinical perspective links obesity to poor health, a shortened life span and to many sociopsychological and lifestyle disorders. An evolutionary perspective, in contrast, views obesity as resulting from variation in genotype and an environment with high-energy-dense food(s). One possibility is that the obese-prone genotype is nonadaptiveFresulting from a coincidence of genetic drift and the high-energy foods of modern humans.5 Alternatively, the obese-prone genotype may be a consequence of adaptation, and obesity is a phenotypic expression of an interaction between genotype (obese-prone vs lean-prone) and environment (high-/lowenergy food supply). The 'thrifty gene' theory of obesity is one form of the adaptive hypothesis. The theory explains how genes favor the efficient use of energy stores in times of feast followed by famine, and result in obesity in the food-rich environment of prosperous societies.6,7Our formulation of the adaptive hypothesis proposes that the obese-prone genotype confers an advantage under conditions of unpredictable changes in food supplyF allowing for storage and conservation of energy and increased foraging during periods of food depletion. In the laboratory, rats on food restriction with the opportunity to (wheel) run show activity anorexiaFa vicious cycle of suppressed food intake, declining body weight and escalating wheel activity leading to starvation and death. 8,9 Compared with lean strains, rats from an obese-prone strain surviv...

Vaccenic acid (VA), the predominant ruminant-derived trans fat in the food chain, ameliorates hyperlipidemia, yet mechanisms remain elusive. We investigated whether VA could influence tissue endocannabinoids (ECs) by altering the availability of their biosynthetic precursor, arachidonic acid (AA), in membrane phospholipids (PLs). JCR:LA-cp rats were assigned to a control diet with or without VA (1% w/w), cis-9, trans-11 conjugated linoleic acid (CLA) (1% w/w) or VA+CLA (1% + 0.5% w/w) for 8 weeks. VA reduced the EC, 2-arachidonoylglycerol (2-AG), in the liver and visceral adipose tissue (VAT) relative to control diet (P < 0.001), but did not change AA in tissue PLs. There was no additive effect of combining VA+CLA on 2-AG relative to VA alone (P > 0.05). Interestingly, VA increased jejunal concentrations of anandamide and those of the noncannabinoid signaling molecules, oleoylethanolamide and palmitoylethanolamide, relative to control diet (P < 0.05). This was consistent with a lower jejunal protein abundance (but not activity) of their degrading enzyme, fatty acid amide hydrolase, as well as the mRNA expression of TNFα and interleukin 1β (P < 0.05). The ability of VA to reduce 2-AG in the liver and VAT provides a potential mechanistic explanation to alleviate ectopic lipid accumulation. The opposing regulation of ECs and other noncannabinoid lipid signaling molecules by VA suggests an activation of benefit via the EC system in the intestine.

Vine DF, Proctor SD. Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cp rat model of prediabetic metabolic syndrome. Am J Physiol Gastrointest Liver Physiol 299: G507-G516, 2010. First published May 27, 2010 doi:10.1152/ajpgi.00173.2010 is a specific antagonist of the cannabinoid-1 receptor. Activation of the receptor initiates multiple effects on central nervous system function, metabolism, and body weight. The hypothesis that rimonabant has protective effects against vascular disease associated with the metabolic syndrome was tested using JCR:LA-cp rats. JCR:LA-cp rats are obese if they are cp/cp, insulin resistant, and exhibit associated micro-and macrovascular disease with end-stage myocardial and renal disease. Treatment of obese rats with rimonabant (10 mg·kg Ϫ1 ·day Ϫ1 , 12-24 wk of age) caused transient reduction in food intake for 2 wk, without reduction in body weight. However, by 4 wk, there was a modest, sustained reduction in weight gain. Glycemic control improved marginally compared with controls, but at the expense of increased insulin concentration. In contrast, rimonabant normalized fasting plasma triglyceride and reduced plasma plasminogen activator inhibitor-1 and acute phase protein haptoglobin in cp/cp rats. Furthermore, these changes were accompanied by reduced postprandial intestinal lymphatic secretion of apolipoprotein B48, cholesterol, and haptoglobin. While macrovascular dysfunction and ischemic myocardial lesion frequency were unaffected by rimonabant treatment, both microalbuminuria and glomerular sclerosis were substantially reduced. In summary, rimonabant has a modest effect on body weight in freely eating obese rats and markedly reduces plasma triglyceride levels and microvascular disease, in part due to changes in intestinal metabolism, including lymphatic secretion of apolipoprotein B48 and haptoglobin. We conclude that rimonabant improves renal disease and intestinal lipid oversecretion associated with an animal model of the metabolic syndrome that appears to be independent of hyperinsulinemia or macrovascular dysfunction. metabolic syndrome; chylomicron overproduction; inflammation; microalbuminuria; glomerular sclerosis; plasminogen activator inhibitor-1; apolipoprotein B48 EXCESSIVE WEIGHT GAIN, PARTICULARLY in the form of abdominal (visceral) adipose tissue, is a major public health problem in prosperous societies worldwide (16,65). The resultant abdominal obesity has driven a developing epidemic of prediabetic insulin resistance and cluster of associated metabolic abnormalities that are termed the metabolic syndrome (9, 35). Insulin resistance leads to chronic hyperinsulinemia and has been implicated as a major determinant of early development of macro-and microvasculopathy, including atherosclerosis, ischemic cardiovascular disease (CVD), and renal damage, which are strongly associated with the metabolic syndrome (9, 26). The contribution of the metabolic syndrome to the development of cardiovascular and re...

Failure of the heat shock response is a key event that leads to insulin resistance and type 2 diabetes. We recently showed that DNAJB3 co-chaperone is downregulated in obese and diabetic patients and that physical exercise restores its normal expression with a significant improvement of the clinical outcomes. In 3T3-L1 adipocytes, DNAJB3 has a role in improving the sensitivity to insulin and glucose uptake. In co-immunoprecipitation assays, DNAJB3 interacts with both JNK1 and IKKβ kinases. However, the functional impact of such interaction on their activities has not been investigated. Here, we assessed the effect of DNAJB3 on the respective activity of JNK1 and IKKβ in cell-based assays. Using JNK1- and IKKβ-dependent luciferase reporters, we show a marked decrease in luciferase activity by DNAJB3 in response to PMA and TNF-α that was consistent with a decrease in the translocation of p65/NF-κB to the nucleus in response to LPS. Furthermore, TNF-α-mediated IL-6 promoter activation and endogenous mRNA expression are significantly abrogated by DNAJB3 both in 3T3-L1 and C2C12 cells. The ability of DNAJB3 to mitigate ER stress and oxidative stress was also investigated and our data show a significant improvement of both forms of stress. Finally, we examined the effect of overexpressing and knocking down the expression of DNAJB3 on glucose uptake in C2C12 as well as the molecular determinants. Accordingly, we provide evidence for a role of DNAJB3 in promoting both basal and insulin-stimulated glucose uptake. Our finding reveals also a novel role of DNAJB3 in eliciting Glut4 translocation to the plasma membrane. These results suggest a physiological role of DNAJB3 in mitigating metabolic stress and improving glucose homeostasis and could therefore represent a novel therapeutic target for type 2 diabetes.

Polycystic Ovary Syndrome (PCOS) is a highly associated with cardiometabolic risk and the metabolic syndrome (MetS), predisposing women to increased risk of developing Type 2 Diabetes and Cardiovascular Disease (CVD). Metformin is commonly used to treat insulin resistance-glucose intolerance, and flutamide, an androgen receptor antagonist, is used to target hyperandrogenemia and dyslipidemia. Currently, the physiological mechanism of action of these treatments on androgen, lipidogenic and insulin signaling pathways remains unclear in the PCOS. The aim of this study was to investigate the effect and mechanism of action of metformin and flutamide on plasma lipid-ApoB-lipoprotein and insulin-glucose metabolism and endocrine-reproductive indices in a PCOS-prone MetS rodent model. PCOS-prone rodents were treated with metformin (300 mg/kg body wt), flutamide (30 mg/kg body wt) or metformin-flutamide for 6 weeks. Metformin was shown to improve fasting insulin and HOMA-IR, whereas flutamide and combination treatment was shown to reduce plasma triglycerides, ApoB48 and ApoB100, and this was associated with decreased intestinal secretion of ApoB48/triglyceride. Flutamide and metformin were shown to reduce plasma androgen indices, and to improve ovarian primary and pre-ovulatory follicle frequency. Metformin treatment, increased hepatic ER-α, and metformin-flutamide decreased intestinal AR and increased ER-α mRNA expression. Metformin-flutamide treatment upregulated hepatic and intestinal insulin signaling including insulin receptor, MAPK1 and AKT2. In conclusion, cardiometabolic risk factors, in particular apoB-hypertriglyceridemia is independently modulated via the AR, and understanding the contribution of AR and insulin-signaling pathways further may facilitate the development of targeted interventions in high-risk women with PCOS and MetS.

No abstract

Low birth weight (LBW) and postnatal nutrition are risk factors for adult metabolic diseases. However, the interactions between LBW, diet, and intestinal lipid absorption and secretion leading to adult metabolic disease remain unclear. The current study determined the impact of LBW on intestinal lipid and carbohydrate metabolism under both control and Western diet (high fat, high fructose, and cholesterol) conditions in 5‐wk‐old LBW and normal birth weight (NBW) Landrace–Large White × Duroc pigs. A 2‐step modified oral glucose and fat challenge test was performed. Mesenteric lymph, jejunal mucosal scrapings, and cecal digesta samples were also collected. LBW offspring were lower in weight and gained less weight per day. LBW pigs on either control or Western diets displayed increased triglyceride (TG) secretion into lymph (P = 0.0135). Western diet‐fed LBW pigs developed fasting (P = 0.03) and postprandial (P < 0.05) hypertriglyceridemia, muscle steatosis (P = 0.0072), had higher insulin excursion (P < 0.01), increased jejunal stearoyl‐CoA desaturase 1 mRNA and increased hepatic fibrosis (P = 0.0017) compared with NBW piglets. Gut microbiota showed significant dysbiosis on Western diet independent of birth weight. In conclusion, LBW pigs fed a Western diet specifically up‐regulate TG absorption and secretion, develop dyslipidemia, muscular steatosis, and display early signs of insulin resistance. Interestingly, this study does not provide evidence of altered intestinal microbiome in LBW pigs contributing to increased severity of metabolic diseases.—Fontaine, M. A., Diane, A., Singh, V. P., Mangat, R., Krysa, J. A., Nelson, R., Willing, B. P., Proctor, S. D. Low birth weight causes insulin resistance and aberrant intestinal lipid metabolism independent of microbiota abundance in Landrace‐Large White pigs. FASEB J. 33, 9250–9262 (2019). http://www.fasebj.org