Control Of Energy Balance Research Articles

Lipin knockdown in pan-neuron of Drosophila induces reduction of lifespan, deficient locomotive behavior, and abnormal morphology of motor neuron

The Lipin family is evolutionarily conserved among insects and mammals, and its crucial roles in lipid synthesis and homeostatic control of energy balance have been well documented. This study investigated the function of Lipin in neuronal function and neurodegeneration. The GAL4/UAS system was used to knock down Lipin in the nervous system of Drosophila and investigate its behavioral and cellular phenotypes. The neuromuscular junction (NMJ) morphology was detected by immunostaining. Moreover, triacylglycerol and ATP levels were analyzed by using assay Kit. This study found that Lipin is localized almost in the cytoplasm of neurons in the brain lobe and ventral nerve cord, which are part of the central nervous system (CNS) of Drosophila melanogaster. Lipin knockdown larvae exhibit decreased locomotor activity, aberrant morphology of motor nerve terminals at NMJs, and reduced number and size of lipid droplets in the CNS. Furthermore, neuron-specific knockdown of Lipin leads to locomotor defects and a shortened lifespan, accompanied by a reduction in ATP levels in the adult stage. These results indicate that Lipin plays a crucial role in the CNS of Drosophila.

A Novel Energy Balance Control Method for a Modular Multilevel Converter in a High-Speed PMSM Drive Application

Nowadays, high-speed permanent magnet synchronous machines (HSPMSMs) are widely used in high-speed direct-drive applications. Moreover, modular multilevel converters (MMCs) have attracted a lot of attention. In this paper, the mathematical model of the MMC for the HSPMSM was built on high- and low-speed regions, respectively, and the control of each model is completely decoupled. Moreover, energy balance control schemes based on the common mode current injection of the MMC with HSPMSM drive applications have been proposed for high- and low-speed cases, respectively. Based on this model, the controller is proposed for high- and low-speed cases, respectively. Simulation and experiment results indicate that the proposed energy balance control method for an MMC in the high-speed PMSM drive application exhibits significant performance, which can ensure the energy balance of the MMC and eliminate the circulating current of the MMC directly.

Microvascular Skeletal-Muscle Crosstalk in Health and Disease.

As an organ system, skeletal muscle is essential for the generation of energy that underpins muscle contraction, plays a critical role in controlling energy balance and insulin-dependent glucose homeostasis, as well as vascular well-being, and regenerates following injury. To achieve homeostasis, there is requirement for "cross-talk" between the myogenic and vascular components and their regulatory factors that comprise skeletal muscle. Accordingly, this review will describe the following: [a] the embryonic cell-signaling events important in establishing vascular and myogenic cell-lineage, the cross-talk between endothelial cells (EC) and myogenic precursors underpinning the development of muscle, its vasculature and the satellite-stem-cell (SC) pool, and the EC-SC cross-talk that maintains SC quiescence and localizes ECs to SCs and angio-myogenesis postnatally; [b] the vascular-myocyte cross-talk and the actions of insulin on vasodilation and capillary surface area important for the uptake of glucose/insulin by myofibers and vascular homeostasis, the microvascular-myocyte dysfunction that characterizes the development of insulin resistance, diabetes and hypertension, and the actions of estrogen on muscle vasodilation and growth in adults; [c] the role of estrogen in utero on the development of fetal skeletal-muscle microvascularization and myofiber hypertrophy required for metabolic/vascular homeostasis after birth; [d] the EC-SC interactions that underpin myofiber vascular regeneration post-injury; and [e] the role of the skeletal-muscle vasculature in Duchenne muscular dystrophy.

Natural products as novel anti-obesity agents: insights into mechanisms of action and potential for therapeutic management.

Obesity affects more than 10% of the adult population globally. Despite the introduction of diverse medications aimed at combating fat accumulation and obesity, a significant number of these pharmaceutical interventions are linked to substantial occurrences of severe adverse events, occasionally leading to their withdrawal from the market. Natural products serve as attractive sources for anti-obesity agents as many of them can alter the host metabolic processes and maintain glucose homeostasis via metabolic and thermogenic stimulation, appetite regulation, pancreatic lipase and amylase inhibition, insulin sensitivity enhancing, adipogenesis inhibition and adipocyte apoptosis induction. In this review, we shed light on the biological processes that control energy balance and thermogenesis as well as metabolic pathways in white adipose tissue browning, we also highlight the anti-obesity potential of natural products with their mechanism of action. Based on previous findings, the crucial proteins and molecular pathways involved in adipose tissue browning and lipolysis induction are uncoupling protein-1, PR domain containing 16, and peroxisome proliferator-activated receptor-γ in addition to Sirtuin-1 and AMP-activated protein kinase pathway. Given that some phytochemicals can also lower proinflammatory substances like TNF-α, IL-6, and IL-1 secreted from adipose tissue and change the production of adipokines like leptin and adiponectin, which are important regulators of body weight, natural products represent a treasure trove for anti-obesity agents. In conclusion, conducting comprehensive research on natural products holds the potential to accelerate the development of an improved obesity management strategy characterized by heightened efficacy and reduced incidence of side effects.

Phase-Shifted Energy Balance Control for Multilevel Inverters in Grid-Connected PV Systems

Cascaded multilevel converters are promising candidates for grid-connected PV systems, but low-frequency ripples may exist in a DC link. Such ripples are not just inherent; they can occur due to environmental factors, such as variations in a certain range of irradiance of the PV. To address this issue, this article proposes a clock phase-shifted (CPS) energy balance control method for grid-connected cascaded multilevel inverters for photovoltaic (PV) systems. The proposed control scheme can prevent the low-frequency ripple of the DC link propagating to the power grid. Furthermore, it is feasible in principle and no adjustment of the control parameters is needed. The simulation and experimental results verify the effectiveness and feasibility of the proposed approach.

Brain-derived neurotrophic factor: Its role in energy balance and cancer cachexia

Brain-derived neurotrophic factor (BDNF) plays an important role in the development of the central and peripheral nervous system during embryogenesis. In the mature central nervous system, BDNF is required for the maintenance and enhancement of synaptic transmissions and the survival of neurons. Particularly, it is involved in the modulation of neurocircuits that control energy balance through food intake, energy expenditure, and locomotion. Regulation of BDNF in the central nervous system is complex and environmental factors affect its expression in murine models which may reflect to phenotype dramatically. Furthermore, BDNF and its high-affinity receptor tropomyosin receptor kinase B (TrkB), as well as pan-neurotrophin receptor (p75NTR) is expressed in peripheral tissues in adulthood and their signaling is associated with regulation of energy balance. BDNF/TrkB signaling is exploited by cancer cells as well and BDNF expression is increased in tumors. Intriguingly, previously demonstrated roles of BDNF in regulation of food intake, adipose tissue and muscle overlap with derangements observed in cancer cachexia. However, data about the involvement of BDNF in cachectic cancer patients and murine models are scarce and inconclusive. In the future, knock-in and/or knock-out experiments with murine cancer models could be helpful to explore potential new roles for BDNF in the development of cancer cachexia.

NPFFR2-deficient mice fed a high-fat diet develop strong intolerance to glucose.

A previous study on neuropeptide FF receptor 2 (NPFFR2)-deficient mice has demonstrated that NPFFR2 is involved in the control of energy balance and thermogenesis. Here, we report on the metabolic impact of NPFFR2 deficiency in male and female mice that were fed either a standard diet (STD) or a high-fat diet (HFD) and each experimental group consisted of ten individuals. Both male and female NPFFR2 knockout (KO) mice exhibited severe glucose intolerance that was exacerbated by a HFD diet. In addition, reduced insulin pathway signaling proteins in NPFFR2 KO mice fed a HFD resulted in the development of hypothalamic insulin resistance. HFD feeding did not cause liver steatosis in NPFFR2 KO mice of either sex, but NPFFR2 KO male mice fed a HFD had lower body weights, white adipose tissues, and liver and lower plasma leptin levels compared with their wild-type (WT) controls. Lower liver weight in NPFFR2 KO male mice compensated for HFD-induced metabolic stress by increased liver PPARα and plasma FGF21 hepatokine, which supported fatty acid β-oxidation in the liver and white adipose tissue. Conversely, NPFFR2 deletion in female mice attenuated the expression of Adra3β and Pparγ, which inhibited lipolysis in adipose tissue.

Energy stress modulation of AMPK/FoxO3 signaling inhibits mitochondria-associated ferroptosis

Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays an important role in cell metabolism, mitochondrial dysfunction and oxidative stress response. Although the AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway plays a pivotal role in maintaining energy homeostasis under conditions of energy stress, the role of AMPK/FoxO3a signaling in mitochondria-associated ferroptosis has not yet been fully elucidated. We show that glucose starvation induced AMPK/FoxO3a activation and inhibited ferroptosis induced by erastin. Inhibition of AMPK or loss of FoxO3a in cancer cells under the glucose starvation condition can sensitize these cells to ferroptosis. Glucose deprivation inhibited mitochondria-related gene expression, reduced mitochondrial DNA(mtDNA) copy number, decreased expression of mitochondrial proteins and lowered the levels of respiratory complexes by inducing FoxO3a. Loss of FoxO3a promoted mitochondrial membrane potential hyperpolarization, oxygen consumption, lipid peroxide accumulation and abolished the protective effects of energy stress on ferroptosis in vitro. In addition, we identified a FDA-approved antipsychotic agent, the potent FoxO3a agonist trifluoperazine, which largely reduced ferroptosis-associated cerebral ischemia-reperfusion (CIR) injuries in rats through AMPK/FoxO3a/HIF-1α signaling and mitochondria-dependent mechanisms. We found that FoxO3a binds to the promoters of SLC7A11 and reduces CIR-mediated glutamate excitotoxicity through inhibiting the expression of SLC7A11. Collectively, these results suggest that energy stress modulation of AMPK/FoxO3a signaling regulates mitochondrial activity and alters the ferroptosis response. The regulation of FoxO3a by AMPK may play a crucial role in mitochondrial gene expression that controls energy balance and confers resistance to mitochondria-associated ferroptosis and CIR injuries.

Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding.

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics' ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) - brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.

GPR-160 Receptor Signaling in the Dorsal Vagal Complex of Male Rats Modulates Meal Microstructure and CART-Mediated Hypophagia.

The g-protein coupled receptor GPR-160, recently identified as a putative receptor for the cocaine and amphetamine-regulated transcript (CART) peptide, shows abundant expression in the energy-balance control nuclei, including the dorsal vagal complex (DVC). However, its physiological role in the control of food intake has yet to be fully explored. Here, we performed a virally mediated, targeted knockdown (KD) of Gpr160 in the DVC of male rats to evaluate its physiological role in control of feeding. Our results indicate that DVC Gpr160 KD affects meal microstructure. Specifically, DVC Gpr160 KD animals consumed more frequent, but shorter meals during the dark phase and showed decreased caloric intake and duration of meals during the light phase. Cumulatively, however, these bidirectional effects on feeding resulted in no difference in body weight gain. We next tested the role of DVC GPR-160 in mediating the anorexigenic effects of exogenous CART. Our results show that DVC Gpr160 KD partially attenuates CART's anorexigenic effects. To further characterize Gpr160+ cells in the DVC, we utilized single-nucleus RNA sequencing data to uncover abundant GPR-160 expression in DVC microglia and only minimal expression in neurons. Altogether, our results suggest that DVC CART signaling may be mediated by Gpr160+ microglia, which in turn may be modulating DVC neuronal activity to control food intake.

Hypothalamic PVN astrocytes fail to properly set glutamate tone in obese mice contributing to impaired glucose metabolism in this condition

The hypothalamus is key in the control of energy balance, but strategies targeting hypothalamic neurons have failed to provide viable options to treat most metabolic diseases. Conversely, the role of astrocytes in systemic metabolic control has remained largely unexplored. Here, we show that obesity promotes anatomically restricted exacerbated Ca 2+ activity in hypothalamic paraventricular nucleus (PVN) astrocytes. Bidirectional chemogenetic manipulation of astrocyte Ca 2+ activity in lean mice stimulated or inhibited the activity of neighboring parvocellular neurons. Importantly, these effects translated into bidirectional regulation of sympathetic activity, glucose metabolism, and energy balance. We found that the astrocyte-mediated effects on PVN neurons were blocked by the glutamate receptor blocker kynurenic acid, and the astrocyte glutamate transport blocker TBOA, suggesting that the astrocyte-neuron signaling and the effects on glucose metabolism involved the astrocytic control of ambient glutamate levels. Notably, we found that TBOA alone stimulated neurons in lean mice but failed to evoke a response in obese mice. This suggests that the astrocyte glutamate transporter activity is impaired in obese mice. Finally, we found that chemogenetic inhibition of astrocyte Ca 2+ activity in obese mice improved glucose metabolism in this condition. Together, our results indicate that exacerbated astrocyte Ca 2+ activity leads to impaired glutamate transporter activity, standing as a likely mechanism contributing to altered PVN neuronal activity and glucose homeostasis during this condition. Collectively, these findings highlight a yet unappreciated role for astrocytes in the direct control of systemic metabolism and suggest potential targets for anti-obesity strategy. NHLBI F32 HL158172 (MKK) NHLBI HL090948 (JES) NINDS NS094640 (JES) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Anatomical mapping of 'angiotensin sensitive' hypothalamic circuits: implications for the neural control of energy balance

The rising incidence of obesity is largely attributed to increased food intake and/or decreased energy expenditure. Increased intake of high-fat diet (HFD) stimulates the renin-angiotensin system and elevates levels of angiotensin II (Ang II). Ang II exerts physiological effects by activating angiotensin type-1 receptors (AT1aR) expressed in a variety of tissues, including the brain. In particular, AT1aR are robustly expressed in the paraventricular nucleus of the hypothalamus (PVN) and prior studies found that the deletion of AT1aR from PVN neurons promotes hyperphagia that exacerbates HFD-induced obesity. Here, we conduct neuroanatomical studies to probe potential mechanism(s) by which neurons within the PVN that express AT1aR (referred to as PVNAT1aR) impact food intake and energy expenditure. The PVNs of mice with expression of Cre-recombinase directed to the AT1aR gene yellow fluorescent protein (eYFP) were injected with a Cre-inducible adeno-associated virus (AAV) synthesizing eYFP. Using this approach, PVNAT1aR can be visualized with the presence of eYFP. Three-weeks later, brains were collected and processed for immunohistochemistry and/or in situ hybridization. Confocal microscopy revealed that PVNAT1aR synthesize corticotropin-releasing hormone (CRH) mRNA and send axonal projections to the median eminence. Intriguingly, we also observed that PVNAT1aR send axon collaterals to the arcuate nucleus of the hypothalamus (ARC), where they form appositions onto neurons that produce proopiomelanocortin (POMC). The firing of POMC neurons is coupled to decreased food intake and we’ve initiated in vivo studies to evaluate whether activation of PVNAT1aR affects feeding behavior and energy expenditure. Cre-inducible AAVs synthesizing the light sensitive opsin, ChR2, and/or eYFP were delivered into the PVN of AT1aR-Cre mice. Subsequently, mice were implanted with a chronic dwelling fiber-optic terminating in the PVN. After recovery, mice were fed either HFD (60%) or standard CHOW for 5 weeks. On the day of the experiment, mice were food deprived during the light phase and food was reintroduced at the onset of the dark phase. Using a randomized within-subject design, PVNAT1aR were optogenetically excited at the onset of the dark phase for 30 min or tethered to a fiber optic cable without light stimulation. Food intake and energy expenditure were measured using a TSE Phenomaster. While our functional studies are ongoing, our anatomical data suggest that PVNAT1aR may comprise a hypothalamic neurocircuit that promotes satiety, and therefore, may be a future therapeutic target for obesity. FAPESP (2019/22767-8, 2022/00977-3): NIH (HL-145028, HL-150750 and HL136595) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Application of direct energy balance control in Supercritical Unit Coordinated Control System

The direct energy balance control strategy is analyzed and combined with the characteristics of supercritical units. The direct energy balance strategy is reconstructed. The reconstructed direct energy balance signal is applied to the boiler master control feedforward in the coordinated control, taking a power plant’s coordinated control system as an example, t. Thus, it is applied to the control of supercritical units, which improves the regulation quality of the control system in a steady and dynamic state, and effectively solves the problems of large fluctuation of mainstream pressure, locked increase, and decrease of load command, frequent withdrawal of coordinated control and unqualified AGC index.

Adrenergic regulation of astroglial aerobic glycolysis and lipid metabolism: Towards a noradrenergic hypothesis of neurodegeneration

Ageing is a key factor in the development of cognitive decline and dementia, an increasing and challenging problem of the modern world. The most commonly diagnosed cognitive decline is related to Alzheimer's disease (AD), the pathophysiology of which is poorly understood. Several hypotheses have been proposed. The cholinergic hypothesis is the oldest, however, recently the noradrenergic system has been considered to have a role as well. The aim of this review is to provide evidence that supports the view that an impaired noradrenergic system is causally linked to AD. Although dementia is associated with neurodegeneration and loss of neurons, this likely develops due to a primary failure of homeostatic cells, astrocytes, abundant and heterogeneous neuroglial cells in the central nervous system (CNS). The many functions that astrocytes provide to maintain the viability of neural networks include the control of ionic balance, neurotransmitter turnover, synaptic connectivity and energy balance. This latter function is regulated by noradrenaline, released from the axon varicosities of neurons arising from the locus coeruleus (LC), the primary site of noradrenaline release in the CNS. The demise of the LC is linked to AD, whereby a hypometabolic CNS state is observed clinically. This is likely due to impaired release of noradrenaline in the AD brain during states of arousal, attention and awareness. These functions controlled by the LC are needed for learning and memory formation and require activation of the energy metabolism. In this review, we address first the process of neurodegeneration and cognitive decline, highlighting the function of astrocytes. Cholinergic and/or noradrenergic deficits lead to impaired astroglial function. Then, we focus on adrenergic control of astroglial aerobic glycolysis and lipid droplet metabolism, which play a protective role but also promote neurodegeneration under some circumstances, supporting the noradrenergic hypothesis of cognitive decline. We conclude that targeting astroglial metabolism, glycolysis and/or mitochondrial processes may lead to important new developments in the future when searching for medicines to prevent or even halt cognitive decline.

Circadian regulation of glutamate release pathways shapes synaptic throughput in the brainstem nucleus of the solitary tract (NTS).

Circadian regulation of autonomic reflex pathways pairs physiological function with the daily light cycle. The brainstem nucleus of the solitary tract (NTS) is a key candidate for rhythmic control of the autonomic nervous system. Here we investigated circadian regulation of NTS neurotransmission and synaptic throughput using patch-clamp electrophysiology in brainstem slices from mice. We found that spontaneous quantal glutamate release onto NTS neurons showed strong circadian rhythmicity, with the highest rate of release during the light phase and the lowest in the dark, that were sufficient to drive day/night differences in constitutive postsynaptic action potential firing. In contrast, afferent evoked action potential throughput was enhanced during the dark and diminished in the light. Afferent-driven synchronous release pathways showed a similar decrease in release probability that did not explain the enhanced synaptic throughput during the night. However, analysis of postsynaptic membrane properties revealed diurnal changes in conductance, which, when coupled with the circadian changes in glutamate release pathways, tuned synaptic throughput between the light and dark phases. These coordinated pre-/postsynaptic changes encode nuanced control over synaptic performance and pair NTS action potential firing and vagal throughput with time of day. KEY POINTS: Vagal afferent neurons relay information from peripheral organs to the brainstem nucleus of the solitary tract (NTS) to initiate autonomic reflex pathways as well as providing important controls of food intake, digestive function and energy balance. Vagally mediated reflexes and behaviours are under strong circadian regulation. Diurnal fluctuations in presynaptic vesicle release pathways and postsynaptic membrane conductances provide nuanced control over NTS action potential firing and vagal synaptic throughput. Coordinated pre-/postsynaptic changes represent a fundamental mechanism mediating daily changes in vagal afferent signalling and autonomic function.

Impact of one-day fasting, ketogenic diet or exogenous ketones on control of energy balance in healthy participants

Oral ketone supplements may mimic the beneficial effects of endogenous ketones on energy metabolism as β-hydroxybutyrate has been proposed to increase energy expenditure and improve body weight regulation. Therefore, our objective was to compare the effects of a one-day isocaloric ketogenic diet, fasting and supplementation with ketone salts on energy expenditure and appetite perception. Eight healthy young adults (4 women, 4 men, age 24±3 years, BMI 24.3±3.1kg/m2) participated in a randomized cross-over trial with four 24 h-interventions in a whole room indirect calorimeter at a physical activity level of 1.65: (i) total fasting (FAST), (ii) isocaloric ketogenic diet (3.1% energy from carbohydrates (CHO), KETO), (iii) isocaloric control diet (47.4% energy from CHO, ISO), and (iv) ISO supplemented with 38.7g/d ketone salts (exogenous ketones, EXO). Effects on serum ketone levels (15 h-iAUC), energy metabolism (total energy expenditure, TEE; sleeping energy expenditure, SEE; macronutrient oxidation) and subjective appetite were measured. Compared to ISO, ketone levels were considerably higher with FAST and KETO and little higher with EXO (all p>0.05). Total and sleeping energy expenditure did not differ between ISO, FAST and EXO whereas KETO increased TEE (+110±54kcal/d vs. ISO, p<0.05) and SEE (+201±90kcal/d vs. ISO, p<0.05). CHO oxidation was slightly decreased with EXO compared to ISO (-48±27g/d, p<0.05) resulting in a positive CHO balance (p<0.05). No differences between the interventions were found for subjective appetite ratings (all p>0.05). A 24 h-ketogenic diet may contribute to maintain a neutral energy balance by increasing energy expenditure. Exogenous ketones in addition to an isocaloric diet did not improve regulation of energy balance. NCT04490226 https://clinicaltrials.gov/.

Mammalian models of diabetes mellitus, with a focus on type 2 diabetes mellitus.

Although no single animal model replicates all aspects of diabetes mellitus in humans, animal models are essential for the study of energy balance and metabolism control as well as to investigate the reasons for their imbalance that could eventually lead to overt metabolic diseases such as type 2 diabetes mellitus. The most frequently used animal models in diabetes mellitus research are small rodents that harbour spontaneous genetic mutations or that can be manipulated genetically or by other means to influence their nutrient metabolism and nutrient handling. Non-rodent species, including pigs, cats and dogs, are also useful models in diabetes mellitus research. This Review will outline the advantages and disadvantages of selected animal models of diabetes mellitus to build a basis for their most appropriate use in biomedical research.

Astrocytic circadian clock control of energy expenditure by transcriptional stress responses in the ventromedial hypothalamus.

Hypothalamic circuits compute systemic information to control metabolism. Astrocytes residing within the hypothalamus directly sense nutrients and hormones, integrating metabolic information, and modulating neuronal responses. Nevertheless, the role of the astrocytic circadian clock on the control of energy balance remains unclear. We used mice with a targeted ablation of the core-clock gene Bmal1 within Gfap-expressing astrocytes to gain insight on the role played by this transcription factor in astrocytes. While this mutation does not substantially affect the phenotype in mice fed normo-caloric diet, under high-fat diet we unmasked a thermogenic phenotype consisting of increased energy expenditure, and catabolism in brown adipose and overall metabolic improvement consisting of better glycemia control, and body composition. Transcriptomic analysis in the ventromedial hypothalamus revealed an enhanced response to moderate cellular stress, including ER-stress response, unfolded protein response and autophagy. We identified Xbp1 and Atf1 as two key transcription factors enhancing cellular stress responses. Therefore, we unveiled a previously unknown role of the astrocytic circadian clock modulating energy balance through the regulation of cellular stress responses within the VMH.

Technologies, strategies, and cautions when deconvoluting genome-wide association signals: FTO in focus.

Genome-wide association studies have revealed a plethora of genetic variants that correlate with polygenic conditions. However, causal molecular mechanisms have proven challenging to fully define. Without such information, the associations are not physiologically useful or clinically actionable. By reviewing studies of the FTO locus in the genetic etiology of obesity, we wish to highlight advances in the field fueled by the evolution of technical and analytic strategies in assessing the molecular bases for genetic associations. Particular attention is drawn to extrapolating experimental findings from animal models and cell types to humans, as well as technical aspects used to identify long-range DNA interactions and their biological relevance with regard to the associated trait. A unifying model is proposed by which independent obesogenic pathways regulated by multiple FTO variants and genes are integrated at the primary cilium, a cellular antenna where signaling molecules that control energy balance convene.

Neurotransmitters in Type 2 Diabetes and the Control of Systemic and Central Energy Balance.

Efficient signal transduction is important in maintaining the function of the nervous system across tissues. An intact neurotransmission process can regulate energy balance through proper communication between neurons and peripheral organs. This ensures that the right neural circuits are activated in the brain to modulate cellular energy homeostasis and systemic metabolic function. Alterations in neurotransmitters secretion can lead to imbalances in appetite, glucose metabolism, sleep, and thermogenesis. Dysregulation in dietary intake is also associated with disruption in neurotransmission and can trigger the onset of type 2 diabetes (T2D) and obesity. In this review, we highlight the various roles of neurotransmitters in regulating energy balance at the systemic level and in the central nervous system. We also address the link between neurotransmission imbalance and the development of T2D as well as perspectives across the fields of neuroscience and metabolism research.