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Free access

Ken K Y Ho

Diet-induced thermogenesis (DIT) is energy dissipated as heat after a meal, contributing 5–15% to total daily energy expenditure (EE). There has been a long interest in the intriguing possibility that a defect in DIT predisposes to obesity. However, the evidence is conflicting; DIT is usually quantified by indirect calorimetry, which does not measure heat. Using gas exchange, indirect calorimetry measures total post-prandial EE, which comprises heat energy produced from brown adipose tissue (BAT) and energy required for processing and storing nutrients. We questioned whether DIT is reliably quantified by indirect calorimetry by employing infrared thermography to independently assess thermogenesis. Thermogenic activity of BAT was stimulated by cold and by a meal that induced a parallel increase in energy production. These stimulatory effects on BAT thermogenesis were inhibited by glucocorticoids. However, glucocorticoids enhanced postprandial EE in the face of reduced BAT thermogenesis and stimulated lipid synthesis. The increase in EE correlated significantly with the increase in lipogenesis. As energy cannot be destroyed (first law of thermodynamics), the energy that would have been dissipated as heat after a meal is channeled into storage. Post-prandial EE is the sum of heat energy that is lost (true DIT) and chemical energy that is stored. Indirect calorimetry does not reliably quantify DIT. When estimated by indirect calorimetry, assumed DIT can be a friend or foe of energy balance. That gas exchange-derived DIT reflects solely energy dissipation as heat is a false assumption likely to explain the conflicting results on the role of DIT in obesity.

Restricted access

Diego Safian, Jan Bogerd and Rüdiger W Schulz

Follicle-stimulating hormone (Fsh) is a major regulator of spermatogenesis, targeting somatic cell functions in the testes. We reported previously that zebrafish Fsh promoted the differentiation of type A undifferentiated spermatogonia (Aund) by stimulating the production of factors that advance germ cell differentiation, such as androgens, insulin-like peptide 3 (Insl3) and insulin-like growth factor 3 (Igf3). In addition, Fsh also modulated the transcript levels of several other genes, including some belonging to the Wnt signaling pathway. Here, we evaluated if and how Fsh utilizes part of the canonical Wnt pathway to regulate the development of spermatogonia. We quantified the proliferation activity and relative section areas occupied by Aund and type A differentiating (Adiff) spermatogonia and we analyzed the expression of selected genes in response to recombinant proteins and pharmacological inhibitors. We found that from the three downstream mediators of Fsh activity we examined, Igf3, but not 11-ketotestosterone or Insl3, modulated the transcript levels of two β-catenin sensitive genes (cyclinD1 and axin2). Using a zebrafish β-catenin signaling reporter line, we showed that Igf3 activated β-catenin signaling in type A spermatogonia and that this activation did not depend on the release of Wnt ligands. Pharmacological inhibition of the β-catenin or of the phosphoinositide 3-kinase (PI3K) pathways revealed that Igf3 activated β-catenin signaling in a manner involving PI3K to promote the differentiation of Aund to Adiff spermatogonia. This mechanism represents an intriguing example for a pituitary hormone like Fsh using Igf signaling to recruit the evolutionary conserved, local β-catenin signaling pathway to regulate spermatogenesis.

Free access

Frank H Bloomfield

As increasing numbers of babies born preterm survive into adulthood, it is becoming clear that, in addition to the well-described risks of neurodevelopmental sequelae, there also are increased risks for non-communicable diseases, including diabetes. Epidemiological studies indicate that risks are increased even for birth at late preterm and early term gestations and for both type 1 and type 2 diabetes. Thus, factors related to preterm birth likely affect development of the fetal and neonatal beta-cell in addition to effects on peripheral insulin sensitivity. These factors could operate prior to preterm birth and be related to the underlying cause of preterm birth, to the event of being born preterm itself, to the postnatal care of the preterm neonate or to a combination of these exposures. Experimental evidence indicates that factors may be operating during all these critical periods to contribute to altered development of beta-cell mass in those born preterm. Greater understanding of how these factors impact upon development of the pancreas may lead to interventions or management approaches that mitigate the increased risk of later diabetes.

Free access

Clara Lefranc, Malou Friederich-Persson, Roberto Palacios-Ramirez and Aurelie Nguyen Dinh Cat

Obesity is a multifaceted, chronic, low-grade inflammation disease characterized by excess accumulation of dysfunctional adipose tissue. It is often associated with the development of cardiovascular (CV) disorders, insulin resistance and diabetes. Under pathological conditions like in obesity, adipose tissue secretes bioactive molecules called ‘adipokines’, including cytokines, hormones and reactive oxygen species (ROS). There is evidence suggesting that oxidative stress, in particular, the ROS imbalance in adipose tissue, may be the mechanistic link between obesity and its associated CV and metabolic complications. Mitochondria in adipose tissue are an important source of ROS and their dysfunction contributes to the pathogenesis of obesity-related type 2 diabetes. Mitochondrial function is regulated by several factors in order to preserve mitochondria integrity and dynamics. Moreover, the renin–angiotensin–aldosterone system is over-activated in obesity. In this review, we focus on the pathophysiological role of the mineralocorticoid receptor in the adipose tissue and its contribution to obesity-associated metabolic and CV complications. More specifically, we discuss whether dysregulation of the mineralocorticoid system within the adipose tissue may be the upstream mechanism and one of the early events in the development of obesity, via induction of oxidative stress and mitochondrial dysfunction, thus impacting on systemic metabolism and the CV system.

Open access

Ismael González-García, Pablo B Martínez de Morentin, Ánxela Estévez-Salguero, Cristina Contreras, Amparo Romero-Picó, Johan Fernø, Rubén Nogueiras, Carlos Diéguez, Manuel Tena-Sempere, Sulay Tovar and Miguel López

Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC.

Free access

Campbell J L Harter, Georgia S Kavanagh and Jeremy T Smith

Kisspeptin is a neuropeptide with a critical role in the function of the hypothalamic–pituitary–gonadal (HPG) axis. Kisspeptin is produced by two major populations of neurons located in the hypothalamus, the rostral periventricular region of the third ventricle (RP3V) and arcuate nucleus (ARC). These neurons project to and activate gonadotrophin-releasing hormone (GnRH) neurons (acting via the kisspeptin receptor, Kiss1r) in the hypothalamus and stimulate the secretion of GnRH. Gonadal sex steroids stimulate kisspeptin neurons in the RP3V, but inhibit kisspeptin neurons in the ARC, which is the underlying mechanism for positive- and negative feedback respectively, and it is now commonly accepted that the ARC kisspeptin neurons act as the GnRH pulse generator. Due to kisspeptin’s profound effect on the HPG axis, a focus of recent research has been on afferent inputs to kisspeptin neurons and one specific area of interest has been energy balance, which is thought to facilitate effects such as suppressing fertility in those with under- or severe over-nutrition. Alternatively, evidence is building for a direct role for kisspeptin in regulating energy balance and metabolism. Kiss1r-knockout (KO) mice exhibit increased adiposity and reduced energy expenditure. Although the mechanisms underlying these observations are currently unknown, Kiss1r is expressed in adipose tissue and potentially brown adipose tissue (BAT) and Kiss1rKO mice exhibit reduced energy expenditure. Recent studies are now looking at the effects of kisspeptin signalling on behaviour, with clinical evidence emerging of kisspeptin affecting sexual behaviour, further investigation of potential neuronal pathways are warranted.

Restricted access

Melody L Allensworth-James, Angela Odle, Anessa Haney, Melanie MacNicol, Angus MacNicol and Gwen Childs

The developing pituitary is a rapidly changing environment that is constantly meeting the physiological demands of the growing organism. During early postnatal development, the anterior pituitary is refining patterns of anterior hormone secretion in response to numerous genetic factors. Our laboratory previously developed a somatotrope leptin receptor (LEPR) deletion mouse model that had decreased lean body mass, disrupted metabolism, decreased GH stores and was GH deficient as an adult. To understand how deletion of LEPR in somatotropes altered GH, we turned our attention to postnatal development. The current study examines GH, PRL, TSH, ACTH, LH and FSH secretion during postnatal days 4, 5, 8, 10 and 15 and compares age and sex differences. The LEPR mutants have dysregulation of GH (P < 0.03) and a reduced developmental prolactin peak in males (P < 0.04) and females (P < 0.002). There were no differences in weight between groups, and the postnatal leptin surge appeared to be normal. Percentages of immunolabeled GH cells were reduced in mutants compared with controls in all age groups by 35–61% in males and 41–44% in females. In addition, we measured pituitary expression of pituitary transcription factors, POU1F1 and PROP1. POU1F1 was reduced in mutant females at PND 10 (P < 0.009) and PND 15 (P < 0.02) but increased in males at PND 10 (P < 0.01). PROP1 was unchanged in female mutants but showed developmental increases at PND 5 (P < 0.02) and PND 15 (P < 0.01). These studies show that the dysfunction caused by LEPR deletion in somatotropes begins as early as neonatal development and involves developing GH and prolactin cells (somatolactotropes).

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You-Hua Xu, Chen-Lin Gao, Heng-Li Guo, Wen-Qian Zhang, Wei Huang, Shan-Shan Tang, Wen-Jun Gan, Yong Xu, Hua Zhou and Quan Zhu

Endotoxemia has been recognized to be closely accompanied with type 2 diabetes mellitus (T2DM) and is responsible for many diabetic complications. Recent study suggests the potential role of butyrate, a short-chain fatty acid (SCFA) from microbiota metabolite, on T2DM. Gut-leak is a key event in diabetic-endotoxemia. To investigate if butyrate could ameliorate diabetic-endotoxemia, both in vivo and in vitro experiments were carried out in the present study. The effect of butyrate supplementation on blood HbA1c and inflammatory cytokines were determined in db/db mice; gut barrier integrity and expression of tight junction proteins were investigated both in vivo and in vitro. Oral butyrate administration significantly decreased blood HbA1c, inflammatory cytokines and LPS in db/db mice; inflammatory cell infiltration was reduced, and gut integrity and intercellular adhesion molecules were increased as detected by HE staining, immunohistochemistry and Western blot. By gut microbiota assay, ratio of Firmicutes:Bacteroidetes for gut microbiota was reduced by butyrate. In Caco-2 cells, butyrate significantly promoted cell proliferation, decreased inflammatory cytokines’ secretion, enhanced cell anti-oxidative stress ability and preserved the epithelial monocellular integrity, which was damaged by LPS. The present findings demonstrated that butyrate supplementation could ameliorate diabetic-endotoxemia in db/db mice via restoring composition of gut microbiota and preserving gut epithelial barrier integrity.

Restricted access

Silva Sütt, Emmelie Cansby, Alexandra Paul, Manoj Amrutkar, Esther Nuñez-Durán, Nagaraj M Kulkarni, Marcus Ståhlman, Jan Borén, Jurga Laurencikiene, Brian W Howell, Sven Enerbäck and Margit Mahlapuu

Whole-body energy homeostasis at over-nutrition critically depends on how well adipose tissue remodels in response to excess calories. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid storage in non-adipose tissue and systemic insulin resistance in the context of nutritional stress. Here, we investigated the role of STK25 in regulation of adipose tissue dysfunction in mice challenged with a high-fat diet. We found that overexpression of STK25 in high-fat-fed mice resulted in impaired mitochondrial function and aggravated hypertrophy, inflammatory infiltration and fibrosis in adipose depots. Reciprocally, Stk25-knockout mice displayed improved mitochondrial function and were protected against diet-induced excessive fat storage, meta-inflammation and fibrosis in brown and white adipose tissues. Furthermore, in rodent HIB-1B cell line, STK25 depletion resulted in enhanced mitochondrial activity and consequently, reduced lipid droplet size, demonstrating an autonomous action for STK25 within adipocytes. In summary, we provide the first evidence for a key function of STK25 in controlling the metabolic balance of lipid utilization vs lipid storage in brown and white adipose depots, suggesting that repression of STK25 activity offers a potential strategy for establishing healthier adipose tissue in the context of chronic exposure to dietary lipids.

Open access

Sara Della Torre, Gianpaolo Rando, Clara Meda, Paolo Ciana, Luisa Ottobrini and Adriana Maggi

Oestrogens are well-known proliferation and differentiation factors that play an essential role in the correct development of sex-related organs and behaviour in mammals. With the use of the ERE-Luc reporter mouse model, we show herein that throughout mouse development, oestrogen receptors (ERs) are active starting from day 12 post conception. Most interestingly, we show that prenatal luciferase expression in each organ is proportionally different in relation to the germ layer of the origin. The luciferase content is highest in ectoderm-derived organs (such as brain and skin) and is lowest in endoderm-derived organs (such as liver, lung, thymus and intestine). Consistent with the testosterone surge occurring in male mice at the end of pregnancy, in the first 2 days after birth, we observed a significant increase in the luciferase content in several organs, including the liver, bone, gonads and hindbrain. The results of the present study show a widespread transcriptional activity of ERs in developing embryos, pointing to the potential contribution of these receptors in the development of non-reproductive as well as reproductive organs. Consequently, the findings reported here might be relevant in explaining the significant differences in male and female physiopathology reported by a growing number of studies and may underline the necessity for more systematic analyses aimed at the identification of the prenatal effects of drugs interfering with ER signalling, such as aromatase inhibitors or endocrine disrupter chemicals.