The role of hypothalamic neuropeptides and BDNF in obesity and the effects of dietary intervention

Obesity is a serious metabolic disorder that has reached epidemic proportions and has produced a heavy financial burden on health care systems worldwide. Obesity is usually induced by excessive energy intake and is highly resistant to treatment by lifestyle intervention. Using a mouse model, this study investigated the role of hypothalamic neuropeptides and neurotrophic factors in diet-induced obesity and obesity reversal by dietary interventions. Furthermore, this study tested the satiating capacity of various protein sources (whey, soy and gluten) through dietary intervention by analysing the meal pattern behaviour of mice. In the first two chapters, the mRNA expression of hypothalamic cocaine- and amphetamine- regulated transcript (CART), brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase B (TrkB) was examined by in situ hybridisation in dietinduced obese (DIO) and resistant (DR) mice following dietary intervention. CART mRNA expression was increased in the arcuate hypothalamic nucleus (Arc) and the paraventricular nucleus (PVN), and was decreased in the dorsomedial hypothalamic nucleus (DM) and lateral hypothalamic area (LH) of DIO mice compared to DR mice. These results demonstrated for the first time that two groups of CART neurons in the hypothalamus are differentially expressed in DIO mice. BDNF/TrkB mRNA expression was decreased in the hippocampus in DIO mice, suggesting a weakened inhibitory control of food intake. In the ventromedial hypothalamic nucleus (VMH), BDNF mRNA expression was lowered in DIO mice even after obesity reversal compared to DR mice. The low level of BDNF expression in the VMH may indicate an intrinsic nature of obese mice which makes them susceptible to overconsumption of a high-fat diet. Furthermore, energy restricted pair-feeding eliminated the differences between vii DIO and DR mice in both body weight and mRNA expression of hypothalamic CART and hippocampal BDNF/TrkB, which suggests that CART and BDNF/TrkB expression are related to body weight changes. The aim of the third chapter was to examine the expression of Arc orexigenic and anorexigenic neuropeptides in response to weight loss after chronic energy intake restriction. DIO and DR mice were placed on an energy restricted diet or continued on their high-fat diet ad libitum. An additional group was fed a low-fat diet throughout the entire study as controls. The results showed that chronic energy restriction corrected the obesity status and decreased plasma leptin in the DIO mice. Chronic energy restriction increased the expression of hypothalamic orexigenic neuropeptide Y (NPY) and agoutirelated protein (AgRP), however, it had no effect on the expression of Arc proopiomelanocortin (POMC) and CART mRNA. These results suggest that orexigenic NPY and AgRP (but not anorexigenic CART and POMC) may contribute to the reestablishment of a body weight set-point after body weight loss. Following on from the above three chapters which investigated the role of hypothalamic neuropeptides and neurotrophic factors in food intake, the fourth chapter investigated the satiating capacities of single or combined whey, soy and gluten protein diets through analysing the meal pattern behaviour of mice. It was found that the whey protein diet potently prolonged intermeal interval and diminished spontaneous meal frequency. This increase in intermeal interval, suggestive of postprandial and postabsorptive satiety effects, is mainly responsible for the inhibition of total energy intake after a whey protein diet. Combinations of whey and gluten caused a lower energy intake, longer inter-meal interval and lower meal number compared to the other paired combinations. Therefore, a combination of whey and gluten may be a better viii formula to provide a high satiety effect and suppress energy intake for antiobesity purposes. In conclusion, this thesis reveals that dietary intervention has a pronounced impact on the gene expression of hypothalamic neuropeptides and neurotrophic factors. High expression of orexigenic neuropeptides NPY/AgRP and low expression of BDNF/TrkB after weight loss may contribute to the recurrence of obesity. Combining dietary protein manipulations for maximising satiety with inhibition of the orexigenic neuropeptides and stimulation of BDNF/TrkB might be critical for potential treatment of obesity and maintenance of weight loss in human obese individuals

Gold-Catalyzed Intermolecular Nitrene Transfer from 2<i>H</i>‑Azirines to Ynamides: A Direct Approach to Polysubstituted Pyrroles

An effective gold-catalyzed intermolecular nitrene transfer by the reaction of 2<i>H</i>-azirines and ynamides is reported, which provides highly substituted pyrroles in a straightforward manner. This transformation proceeds under mild conditions and gives the polysubstituted pyrroles in good-to-excellent yields. Preliminary results indicate that a nongold carbenoid pathway is preferred for current pyrrole synthesis

Polysubstituted 2‑Aminopyrrole Synthesis via Gold-Catalyzed Intermolecular Nitrene Transfer from Vinyl Azide to Ynamide: Reaction Scope and Mechanistic Insights

A gold-catalyzed intermolecular reaction of vinyl azides and ynamides is described. This process presents an efficient and mild approach to multisubstituted 2-aminopyrroles in good-to-excellent yields. Control experiments were carried out to distinguish the reactivity between vinyl azides and the corresponding 2<i>H</i>-azirines. A plausible reaction mechanism was also proposed according to previous reports and our preliminary mechanistic studies

Palladium-Catalyzed Three-Component Selective Aminoallylation of Diazo Compounds

We describe a Xantphos-containing dinuclear palladium complex-enabled geminal aminoallylation of diazocarbonyl compounds, which selectively provides a range of quaternary α-amino esters. Direct N–H insertion, allylic alkylation of amino nucleophiles, and diene formation were not observed under standard conditions. Mechanistic studies indicated that a relayed pathway via allylation of the N–H insertion product or [2,3]-sigmatropic rearrangement of an ylide intermediate was unlikely

Chronic Rb1 treatment reduced hypothalamic inflammation and negative regulators of leptin signaling in obese mice.

<p>Chronic treatment of Rb1 significantly decreased the level of IL-6 (A), IL-1β (B), p-IKK (D), SOCS3 (E) and PTP1B (F) in the mediobasal hypothalamus of obese mice (n = 6–8) fed a HF diet for 16 weeks without leptin icv injection. Panel C: HF diet significantly increased the protein levels of TNFα in the mediobasal hypothalamus of mice. *<i>p</i><0.05 vs HF group, #<i>p</i><0.05 vs. LC lean control. Data are presented as mean ± SEM.</p

Divergent Access to Polycyclic <i>N</i>‑Heterocyclic Compounds through Büchner-Type Dearomatization Enabled Cycloisomerization of Diynamides under Gold Catalysis

Catalytic dearomatization has been considered as a valuable approach to convert readily accessible flat molecules to products with three-dimensional frameworks. Herein, an unprecedented gold-catalyzed oxidative Büchner-type cyclopropanation is described that enables the cycloisomerization of diynamides. By variation of the position of substituents on the phenyl ring, a variety of fused N-heterocyclic products with challenging structural skeletons were obtained divergently

Polysubstituted 2‑Aminopyrrole Synthesis via Gold-Catalyzed Intermolecular Nitrene Transfer from Vinyl Azide to Ynamide: Reaction Scope and Mechanistic Insights

A gold-catalyzed intermolecular reaction of vinyl azides and ynamides is described. This process presents an efficient and mild approach to multisubstituted 2-aminopyrroles in good-to-excellent yields. Control experiments were carried out to distinguish the reactivity between vinyl azides and the corresponding 2<i>H</i>-azirines. A plausible reaction mechanism was also proposed according to previous reports and our preliminary mechanistic studies

Chronic Rb1 treatment improved central leptin sensitivity in obese mice fed a HF diet for 16 weeks.

<p>Energy intake (A–C) and body weight gain (D–F) for 24 hours after the icv injection of leptin or saline in mice fed a LC diet (n = 7–8), in obese mice fed a HF diet for 8 weeks with or without acute treatment of Rb1 (14 mg/kg ip daily for 2 days) (n = 7–8), in obese mice fed a HF diet for 16 weeks with or without chronic treatment of Rb1 (14 mg/kg ip daily for 21 days) (n = 7–8). *<i>p</i><0.05 vs. (Vehicle + Saline) group; ^#<i>p</i><0.05 vs. (Vehicle + leptin) group; and ⁺<i>p</i><0.05 vs. (Rb1 + Saline) group. Data are presented as mean ± SEM.</p

Central Inflammation and Leptin Resistance Are Attenuated by Ginsenoside Rb1 Treatment in Obese Mice Fed a High-Fat Diet

<div><p>A low-grade pro-inflammatory state is at the pathogenic core of obesity and type 2 diabetes. We tested the hypothesis that the plant terpenoid compound ginsenoside Rb1 (Rb1), known to exert anti-inflammatory effects, would ameliorate obesity, obesity-associated inflammation and glucose intolerance in the high-fat diet-induced obese mouse model. Furthermore, we examined the effect of Rb1 treatment on central leptin sensitivity and the leptin signaling pathway in the hypothalamus. We found that intraperitoneal injections of Rb1 (14 mg/kg, daily) for 21 days significantly reduced body weight gain, fat mass accumulation, and improved glucose tolerance in obese mice on a HF diet compared to vehicle treatment. Importantly, Rb1 treatment also reduced levels of pro-inflammatory cytokines (TNF-α, IL-6 and/or IL-1β) and NF-κB pathway molecules (p-IKK and p-IκBα) in adipose tissue and liver. In the hypothalamus, Rb1 treatment decreased the expression of inflammatory markers (IL-6, IL-1β and p-IKK) and negative regulators of leptin signaling (SOCS3 and PTP1B). Furthermore, Rb1 treatment also restored the anorexic effect of leptin in high-fat fed mice as well as leptin pSTAT3 signaling in the hypothalamus. Ginsenoside Rb1 has potential for use as an anti-obesity therapeutic agent that modulates obesity-induced inflammation and improves central leptin sensitivity in HF diet-induced obesity.</p></div

Chronic Rb1 treatment reduced peripheral inflammation in obese mice fed a HF diet for 16 weeks.

<p>Protein expression of the pro-inflammatory cytokines TNF-α, IL-6 and IL-1β, as well as the inflammatory signaling molecules p-IKK and p-IκBα in the epididymal fat tissue (A) and liver (B) in HF-induced obese mice with Rb1 chronic treatment (n = 8). *<i>p</i><0.05 vs. HF diet control group, +<i>p</i><0.10 and >0.05 vs. HF control group. Data are presented as mean ± SEM.</p