Dietary modulation of adipose tissue and cardiometabolic health

Obesity has a great societal impact as it contributes to the development of type 2 diabetes and cardiovascular diseases. Activation of brown adipose tissue (BAT) is seen as a strategy to combat adiposity and related disorders, because of its capacity to combust nutrients and increase energy expenditure. To develop novel BAT activating methods, a better understanding of the pathophysiology of diet-induced obesity on BAT function and whole-body metabolism is required. Studies described in this thesis have increased our understanding of nutrient handling by brown adipocytes. We also generated immortalized brown adipocytes which can be used for future research. Furthermore, we gained more insight into the development of diet-induced obesity; feeding a high fat diet (HFD) rapidly made BAT insulin resistant and less active. In addition, HFD feeding increased synthesis of so-called endocannabinoids in both white and brown adipose tissue. Because endocannabinoids regulate both energy intake and expenditure, future research should determine whether inhibiting endocannabinoid signaling specifically in adipose tissue is a worthwhile strategy to pursue in combating obesity. Finally, quercetin, which naturally occurs in fruits and vegetables, induced ‘browning’ of white adipose tissue and thereby improved blood lipid levels. These studies pave the road for further development of BAT-activating strategies! Rembrandt Institute of Cardiovascular Science (RICS) Dutch Heart FoundationLUMC / Geneeskund

A two-component signal-transduction cascade in Carnobacterium piscicola LV17B:two signaling peptides and one sensor-transmitter

In the lactic acid bacterium Carnobacterium piscicola LV17B a peptide-pheromone dependent quorum-sensing mode is involved in the regulation of bacteriocin production. Bacteriocin CB2 was identified as an environmental signal that induces bacteriocin production. Here, we demonstrate that a second 24 amino acid peptide (CS) also induces bacteriocin production. Transcription activation of several carnobacteriocin operons is triggered by CB2 or CS via a two-component signal transduction system composed of CbnK and CbnR. (C) 2001 Elsevier Science Inc. All rights reserved

Absence of Self-Averaging and Universal Fluctuations in Random Systems Near Critical Points

The distributions P(X) of singular thermodynamic quantities, on an ensemble of d-dimensional quenched random samples of linear size L near a critical point, are analyzed using the renormalization group. For L much larger than the correlation length ξ, we recover strong self-averaging (SA): P(X) approaches a Gaussian with relative squared width RX~(L/ξ)−d. For L≪ξ we show weak SA (RX decays with a small power of L) or no SA [P(X) approaches a non-Gaussian, with universal L-independent relative cumulants], when the randomness is irrelevant or relevant, respectively

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of beta-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gscoupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.Diabetes mellitus: pathophysiological changes and therap

Extracellular factors regulating MBP expression in oligodendrocytes. And how it’s deregulated in multiple sclerosis.

Multilayered myelin sheaths surround axons in the CNS and are required for saltatory conduction. Persistent disturbance of myelin formation leads to several brain diseases, including multiple sclerosis (MS). In MS, an inflammation-mediated event results in demyelination, and ultimate failure of remyelination and axonal loss cause disease progression. The myelin sheath extends from processes of oligodendrocytes. The most prominent and crucial protein in myelin biogenesis is myelin basic protein (MBP). MBP facilitates compaction by stabilizing the inner leaflets of the membranes. To prevent ectopic expression, MBP is transported to the processes as mRNA in specific granules where it is translated ‘on site’. Myelin biogenesis is exogenous regulated by many inhibiting or stimulating factors that can be divided in contact-dependent factors and soluble factors. In the present report, these factors are described in association to MBP expression. The regulation during developmental myelination is compared with the regulation in MS lesions, followed by suggestions for therapeutic targets that aim for enhanced and correct MBP expression and thereby remyelination in MS.

Dietary modulation of adipose tissue and cardiometabolic health

Obesity has a great societal impact as it contributes to the development of type 2 diabetes and cardiovascular diseases. Activation of brown adipose tissue (BAT) is seen as a strategy to combat adiposity and related disorders, because of its capacity to combust nutrients and increase energy expenditure. To develop novel BAT activating methods, a better understanding of the pathophysiology of diet-induced obesity on BAT function and whole-body metabolism is required. Studies described in this thesis have increased our understanding of nutrient handling by brown adipocytes. We also generated immortalized brown adipocytes which can be used for future research. Furthermore, we gained more insight into the development of diet-induced obesity; feeding a high fat diet (HFD) rapidly made BAT insulin resistant and less active. In addition, HFD feeding increased synthesis of so-called endocannabinoids in both white and brown adipose tissue. Because endocannabinoids regulate both energy intake and expenditure, future research should determine whether inhibiting endocannabinoid signaling specifically in adipose tissue is a worthwhile strategy to pursue in combating obesity. Finally, quercetin, which naturally occurs in fruits and vegetables, induced ‘browning’ of white adipose tissue and thereby improved blood lipid levels. These studies pave the road for further development of BAT-activating strategies! </table

Quorum sensing by peptide pheromones and two-component signal-transduction systems in Gram-positive bacteria

Cell-density-dependent gene expression appears to be widely spread in bacteria. This quorum-sensing phenomenon has been well established in Gram-negative bacteria, where N-acyl homoserine lactones are the diffusible communication molecules that modulate cell-density-dependent phenotypes. Similarly, a variety of processes are known to be regulated in a cell-density- or growth-phase-dependent manner in Gram-positive bacteria. Examples of such quorum-sensing modes in Gram-positive bacteria are the development of genetic competence in Bacillus subtilis and Streptococcus pneumoniae, the virulence response in Staphylococcus aureus, and the production of antimicrobial peptides by several species of Gram-positive bacteria including lactic acid bacteria. Cell-density-dependent regulatory modes in these systems appear to follow a common theme, in which the signal molecule is a post-translationally processed peptide that is secreted by a dedicated ATP-binding-cassette exporter. This secreted peptide pheromone functions as the input signal for a specific sensor component of a two-component signal-transduction system. Moreover, genetic linkage of the common elements involved results in autoregulation of peptide-pheromone production.

A two-component signal-transduction cascade in Carnobacterium piscicola LV17B: two signaling peptides and one sensor-transmitter

In the lactic acid bacterium Carnobacterium piscicola LV17B a peptide-pheromone dependent quorum-sensing mode is involved in the regulation of bacteriocin production. Bacteriocin CB2 was identified as an environmental signal that induces bacteriocin production. Here, we demonstrate that a second 24 amino acid peptide (CS) also induces bacteriocin production. Transcription activation of several carnobacteriocin operons is triggered by CB2 or CS via a two-component signal transduction system composed of CbnK and CbnR.

Maximizing Authentic Learning and Real-World Problem-solving in Health Curricula Through Psychological Fidelity in a Game-Like Intervention: Development, Feasibility, and Pilot Studies

High fidelity is regarded as a hallmark of educational games and simulations for health education. Mainly physical and functional fidelity are associated with authenticity, resulting in the pursuit of a true-to-life simulation and suggesting the imposition of a generally accepted and often unintentional design rationale that assumes that the greater the fidelity of a game or simulation to the real world, the more authentic the intervention is perceived as. Psychological fidelity receives significantly less attention, although it correlates strongly to credibility, suspension of disbelief, and engagement. The BABLR simulator reduces physical and functional fidelity to a minimum and explores the use of psychological fidelity as the main carrier of an authentic learning experience. BABLR was assessed using 26 participants with varying backgrounds in health innovation and social work. In several pilot studies, we collected data on perceived realisticness and real-world relevance. Results show that experts, as well as participants, attest to BABLR’s engagement, immersiveness, and motivational qualities. Practical implications of these findings for future research into developing low-fidelity simulations with high psychological fidelity will be discussed.Accepted author manuscriptDesign Aesthetic

IL-37 Expression Reduces Lean Body Mass in Mice by Reducing Food Intake

The human cytokine interleukin (IL)-37 is an anti-inflammatory member of the IL-1 family of cytokines. Transgenic expression of IL-37 in mice protects them from diet-induced obesity and associated metabolic complications including dyslipidemia, inflammation and insulin resistance. The precise mechanism of action leading to these beneficial metabolic effects is not entirely known. Therefore, we aimed to assess in detail the effect of transgenic IL-37 expression on energy balance, including food intake and energy expenditure. Feeding homozygous IL-37 transgenic mice and wild-type (WT) control mice a high-fat diet (HFD; 45% kcal palm fat) for 6 weeks showed that IL-37 reduced body weight related to a marked decrease in food intake. Subsequent mechanistic studies in mice with heterozygous IL-37 expression versus WT littermates, fed the HFD for 18 weeks, confirmed that IL-37 reduces food intake, which led to a decrease in lean body mass, but did not reduce fat mass and plasma lipid levels or alterations in energy expenditure independent of lean body mass. Taken together, this suggests that IL-37 reduces lean body mass by reducing food intake