Role of secretin in lipid homeostasis

Secretin, the first hormone commencing the field of endocrinology, has been studied for its pleiotropic role in the body inclusive of its neuroactive and body water homeostatic and gastrointestinal functions. Yet, the metabolic effect of secretin remains elusive and is being proposed recently for a revisit. Recent discovery from our lab showed an anorectic response for secretin, while its role in lipid homeostasis remains largely unexplored. Exerting functions such as exocrine pancreatic secretion and gastric motility inhibition, intestinal fatty acid induced release of secretin was recently shown to be mediated by CD36. Fasting related increase in plasma secretin concentration has been proposed to be involved in lipolysis but evidences regarding lipolytic actions of secretin remain contradictory. Recent report has suggested that secretin stimulates both lipolysis and lipogenesis in adipose cells. Thus, we hypothesize that secretin modulates lipid homeostasis, which was examined under two opposite, energy deficient and energy excess, conditions. Under energy deficient/starved state, secretin level in circulation and secretin receptor level in epididymal adipose tissue were found to be upregulated. Using secretin receptor knockout (SCTR-/-) and secretin knockout (SCT-/-) mice as controls, it was found that secretin stimulated a dose- and time-dependent lipolysis in vitro and acute lipolysis in vivo. H-89, a protein kinase A (PKA) inhibitor, attenuated the lipolytic effects of secretin in vitro, while secretin induced an increase in cAMP dependent PKA activity in vivo. Using western blot analysis, secretin was found to phosphorylate hormone sensitive lipase (HSL) at serine residue 660. Additionally, immunofluorescent studies revealed that secretin stimulated translocation of HSL from cytosol to surface of lipid droplet subsequently leading to lipolysis. Under excess energy condition, when SCTR-/- mice and its littermates SCTR+/+ mice were subjected to high fat diet (HFD) feeding for 3 months, it was found that SCTR-/- mice gained lesser weight. Nuclear magnetic resonance imaging revealed that SCTR-/- mice exhibited lower body fat content. Additionally, HFD-associated hyperleptinaemia was alleviated in SCTR-/- mice along with metabolic syndrome as they performed better in insulin and glucose tolerance tests. Continuous monitoring by indirect calorimetry revealed similar food intake, energy expenditure and locomotor activity between SCTR-/- and SCTR+/+ mice. Interestingly, intestinal fatty acid absorption, measured by a noninvasive method, was impaired in HFD-fed SCTR-/- mice. While postprandial triglyceride release was reduced in SCTR-/- mice, it also had a significant reduction in transcript and protein levels of CD36 and its downstream mediator MTTP. Secretin, when incubated with isolated enterocytes, upregulated the expression of CD36. In summary, during starvation, secretin stimulates lipolysis through a HSL and PKA mediated pathway. When fed a HFD, SCTR-/- mice is resistant to diet induced obesity due to impaired intestinal lipid absorption. A novel short positive feedback pathway between CD36 and secretin, functioning to maximize lipid absorption, is also being proposed. Thus for the first time, two independent role of secretin in lipolysis and in intestinal lipid absorption were discovered along with their mechanistic insights. This study paves way for developing new therapeutic strategies against metabolic disorders associated with lipid metabolism.published_or_final_versionBiological SciencesDoctoralDoctor of Philosoph

Corrigendum: Central Control of Feeding Behavior by the Secretin, PACAP, and Glucagon Family of Peptides

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Prediction of factors for Controlling of Green House Farming with Fuzzy based multiclass Support Vector Machine

A smart greenhouse is a scheme with the aim of allowing the plant growth optimally due to the control in temperature, soil moisture, and humidity. It is necessary to go for best possible smart greenhouse controlling system to maneuver the parameters in accordance with the climatic and seasonal changes plant. In this proposed work, the appropriate setting, monitoring of the model parameters like optimal temperature, humidity, and soil moisture in the greenhouse farm available at Modakkurichi near Erode is carried out using fuzzy logic and multiclass Support Vector Machine (SVM) techniques. It is efficiently implemented as the fuzzy trapezoidal membership function for each sample within the hyper-sphere as a linear function of the selected sample’s distance in the non-linear SVM hyperplane. Based on the simulation and experimental results, the fuzzy logic with Multi-class Support Vector Machine method is effective in selection of the rules to make decision. Simulation of the work was carried out in Python using the open source tool COLAB. Statistical parameters are evaluated for the proposed Fuzzy based SVM method. Root Mean Square Error of the proposed controller has the minimum value as 0.962E-02 when compared to other controllers which vary from 1.04 E-02 to 8.27 E-02

Vagal afferent mediates the anorectic effect of peripheral secretin.

Secretin (SCT) is a classical peptide hormone that is synthesized and released from the gastrointestinal tract after a meal. We have previously shown that it acts both as a central and peripheral anorectic peptide, and that its central effect is mediated via melanocortin system. As peripheral satiety signals from the gastrointestinal tract can be sent to the brain via the vagal afferent or by crossing the blood-brain barrier (BBB), we therefore sought to investigate the pathway by which peripheral SCT reduces appetite in this study. It is found that bilateral subdiaphragmatic vagotomy and treatment of capsaicin, an excitotoxin for primary afferent neurons, could both block the anorectic effect of peripherally injected SCT. These treatments are found to be capable of blunting i.p. SCT-induced Fos activation in pro-opiomelanocortin (POMC) neurons within the hypothalamic Arcuate Nucleus (Arc). Moreover, we have also found that bilateral midbrain transaction could block feeding reduction by peripheral SCT. Taken together, we conclude that the satiety signals of peripheral SCT released from the gastrointestinal tract are sent via the vagus nerves to the brainstem and subsequently Arc, where it controls central expression of other regulatory peptides to regulate food intake

Glucagon's metabolic action in health and disease

Discovered almost simultaneously with insulin, glucagon is a pleiotropic hormone with metabolic action that goes far beyond its classical role to increase blood glucose. Albeit best known for its ability to directly act on the liver to increase de novo glucose production and to inhibit glycogen breakdown, glucagon lowers body weight by decreasing food intake and by increasing metabolic rate. Glucagon further promotes lipolysis and lipid oxidation and has positive chronotropic and inotropic effects in the heart. Interestingly, recent decades have witnessed a remarkable renaissance of glucagon’s biology with the acknowledgment that glucagon has pharmacological value beyond its classical use as rescue medication to treat severe hypoglycemia. In this article, we summarize the multifaceted nature of glucagon with a special focus on its hepatic action and discuss the pharmacological potential of either agonizing or antagonizing the glucagon receptor for health and disease

Glycyrrhizic Acid Reduces Heart Rate and Blood Pressure by a Dual Mechanism

Beta adrenergic receptors are crucial for their role in rhythmic contraction of heart along with their role in the pathological conditions such as tachycardia and high risk of heart failure. Studies report that the levels of beta-1 adrenergic receptor tend to decrease by 50%, whereas, the levels of beta-2 adrenergic receptor remains constant during the risk of heart failure. Beta blockers—the antagonistic molecules for beta-adrenergic receptors, function by slowing the heart rate, which thereby allows the left ventricle to fill completely during tachycardia incidents and hence helps in blood pumping capacity of heart and reducing the risk of heart failure. In the present study, we investigate the potential of glycyrrhizic acid (GA) as a possible principal drug molecule for cardiac arrhythmias owing to its ability to induce reduction in the heart rate and blood pressure. We use in vitro and in silico approach to study GA′s effect on beta adrenergic receptor along with an in vivo study to examine its effect on heart rate and blood pressure. Additionally, we explore GA′s proficiency in eliciting an increase in the plasma levels of vasoactive intestinal peptide, which by dilating the blood vessel consequently, can be a crucial aid during the occurrence of a potential heart attack. Therefore, we propose GA as a potential principal drug molecule via its potential in modulating heart rate and blood pressure

The effect of vagotomy, capsaicin treatment, and sham operation on SCT-induced Fos expression in POMC neurons.

<p> Bars, 80 µm.</p

Effect of vagotomy (A,C) and capsaicin treatment (B,D) on i.p. 5 nmol SCT (A,B)- and i.c.v. 0.15 nmol SCT (C,D)-induced food intake.

<p>Food intake amount were represented as cumulative value at different time points (1, 2, 4, 6, and 8 h) after SCT treatment. Data are expressed as the means ± SEM (n = 10/group). * p<0.05, ** p<0.01 compared with the sham-operated mice injected with i.p.-PBS/i.c.v.-aCSF. • p<0.05, •• p<0.01 compared with surgical/chemical-treated mice injected with i.p.-PBS/i.c.v.-aCSF.</p