Control Of Energy Expenditure Research Articles

Estrogenic re-mapping of the metabolic response to an energy deficit

Endothermy is an adaptation that can be traced back hundreds of millions of years and is critical for nearly every aspect of mammalian biology. Despite the advantages associated with a stable internal temperature, endothermy is energetically expensive. To conserve energy when food is scarce, mice have evolved the ability to reversibly enter a regulated state of hypothermia and hypometabolism, known as torpor. We have found that circulating 17β-estradiol, a potent estrogen, inhibits fasting-induced torpor in ovariectomized female mice, yet the signaling mechanisms underlying this estrogenic re-mapping of the metabolic response to an energy deficit remain largely unknown. Recent studies have identified the medial preoptic area of the hypothalamus (MPO) as the central regulator of torpor. MPO neurons that express estrogen receptor alpha have been identified as central coordinators of torpor, and MPO neurons that are activated during torpor broadly express estrogen receptors, suggesting that circulating estrogens may directly modulate torpor-driving neurons in the MPO. To test the hypothesis that circulating estrogens inhibit torpor by acting directly on estrogen-sensitive neurons in the MPO, we delivered 17β-estradiol (E2) directly to the MPO before inducing torpor with a 48-hour fast. Surprisingly, we found that E2 delivered to the MPO was suffcient to inhibit fasting-induced torpor in gonad-intact, but not ovariectomized, female mice. These data demonstrate that E2 signaling in the MPO is insuffcient to inhibit torpor on its own and that there are likely MPO-independent nodes in the body that circulating estrogens act on to inhibit torpor. However, our data also demonstrate that E2 signaling in the MPO does play a role in tuning the torpor response when endogenous gonadal hormones are present, suggesting that the MPO can sense estrogens and engage the appropriate effector circuits to inhibit torpor in certain physiological contexts. Together, these data advance our understanding of how circulating estrogens inhibit torpor in mice — a critical step towards the broader goal of understanding how circulating estrogens influence energy expenditure, and how these pathways can be manipulated to improve metabolic health. NIH RO1 (R01AG066821) - "Estrogenic modulation of neural circuits that control temperature" AHA Predoctoral Fellowship (23PRE1019923) - Estrogenic modulation of hypothalamic neurons that control energy expenditure. This is the full abstract presented at the American Physiology Summit 2024 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.

Apolipoprotein A-IV and its derived peptide, T55−121, improve glycemic control and increase energy expenditure

Abstract It is crucial to understand the glucose control within our bodies. Bariatric/metabolic surgeries, including laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB), provide an avenue for exploring the potential key factors involved in maintaining glucose homeostasis since these surgeries have shown promising results in improving glycemic control among patients with severe type 2 diabetes (T2D). For the first time, a markedly altered population of serum proteins in patients after LSG was discovered and analyzed through proteomics. Apolipoprotein A-IV (apoA-IV) was revealed to be increased dramatically in diabetic obese patients following LSG, and a similar effect was observed in patients after RYGB surgery. Moreover, recombinant apoA-IV protein treatment was proven to enhance insulin secretion in isolated human islets. These results showed that apoA-IV may play a crucial role in glycemic control in humans, potentially through enhancing insulin secretion in human islets. ApoA-IV was further shown to enhance energy expenditure and improve glucose tolerance in diabetic rodents, through stimulating glucose-dependent insulin secretion in pancreatic β cells, partially via Gαs-coupled GPCR/cAMP (G protein-coupled receptor/cyclic adenosine monophosphate) signaling. Furthermore, T55−121, truncated peptide 55−121 of apoA-IV, was discovered to mediate the function of apoA-IV. These collective findings contribute to our understanding of the relationship between apoA-IV and glycemic control, highlighting its potential as a biomarker or therapeutic target in managing and improving glucose regulation.

Resting energy expenditure, body composition, and metabolic alterations in breast cancer survivors vs. healthy controls: a cross-sectional study

PurposeThis study aimed to investigate the difference in absolute and fat free mass (FFM)-adjusted resting energy expenditure (mREE) and body composition (body weight, fat mass (FM), FFM) between breast cancer survivors (BCs) and controls. Correlations with body composition were analyzed. We examined if survival year, or being metabolically dysfunctional were predictive variables.MethodsA cross-sectional analysis was conducted on 32 BCs ≤5 years post treatment and 36 healthy controls. Indirect calorimetry measured absolute mREE. Body composition was determined by BOD POD. FFM-adjusted mREE was calculated (mREE/FFM). The Harris-Benedict equation was used to predict REE and determine hyper−/hypometabolism (mREE/pREE). The database of the multidisciplinary breast clinic of the University Hospital of Antwerp was consulted for survival year and metabolic dysfunctions.ResultsBCs have similar absolute mREE and greater FFM-adjusted mREE compared to controls. Absolute mREE and body composition between BCs differed; adjusted mREE was similar. FFM correlated significantly with absolute mREE in BCs. A significant interaction term was found between survival year and FM for absolute mREE.ConclusionBCs have similar absolute mREE, but higher FFM-adjusted mREE. Differences in body composition between BCs are suggested to cause inter-individual variations. We suggest that increased FFM-adjusted mREE is caused by metabolic stress related to cancer/treatment. Accurate measurement of REE and body composition is advised when adapting nutritional strategies, especially in patients at risk for developing metabolic dysfunctions.

Adaptive optimal control of under-actuated robotic systems using a self-regulating nonlinear weight-adjustment scheme: Formulation and experimental verification.

This paper formulates an innovative model-free self-organizing weight adaptation that strengthens the robustness of a Linear Quadratic Regulator (LQR) for inverted pendulum-like mechatronic systems against perturbations and parametric uncertainties. The proposed control procedure is devised by using an online adaptation law to dynamically adjust the state weighting factors of LQR's quadratic performance index via pre-calibrated state-error-dependent hyperbolic secant functions (HSFs). The updated state-weighting factors re-compute the optimal control problem to modify the state-compensator gains online. The novelty of the proposed article lies in adaptively adjusting the variation rates of the said HSFs via an auxiliary model-free online self-regulation law that uses dissipative and anti-dissipative terms to flexibly re-calibrate the nonlinear function's waveforms as the state errors vary. This augmentation increases the controller's design flexibility and enhances the system's disturbance rejection capacity while economizing control energy expenditure under every operating condition. The proposed self-organizing LQR is analyzed via customized hardware-in-loop (HIL) experiments conducted on the Quanser's single-link rotational inverted pendulum. As compared to the fixed-gain LQR, the proposed SR-EM-STC delivers an improvement of 52.2%, 16.4%, 55.2%, and 42.7% in the pendulum's position regulation behavior, control energy expenditure, transient recovery duration, and peak overshoot, respectively. The experimental outcomes validate the superior robustness of the proposed scheme against exogenous disturbances.

Gut microbiota in overweight and obesity: crosstalk with adipose tissue.

Overweight and obesity are characterized by excessive fat mass accumulation produced when energy intake exceeds energy expenditure. One plausible way to control energy expenditure is to modulate thermogenic pathways in white adipose tissue (WAT) and/or brown adipose tissue (BAT). Among the different environmental factors capable of influencing host metabolism and energy balance, the gut microbiota is now considered a key player. Following pioneering studies showing that mice lacking gut microbes (that is, germ-free mice) or depleted of their gut microbiota (that is, using antibiotics) developed less adipose tissue, numerous studies have investigated the complex interactions existing between gut bacteria, some of their membrane components (that is, lipopolysaccharides), and their metabolites (that is, short-chain fatty acids, endocannabinoids, bile acids, aryl hydrocarbon receptor ligands and tryptophan derivatives) as well as their contribution to the browning and/or beiging of WAT and changes in BAT activity. In this Review, we discuss the general physiology of both WAT and BAT. Subsequently, we introduce how gut bacteria and different microbiota-derived metabolites, their receptors and signalling pathways can regulate the development of adipose tissue and its metabolic capacities. Finally, we describe the key challenges in moving from bench to bedside by presenting specific key examples.

Abdominal aerobic endurance exercise reveals spot reduction exists: A randomized controlled trial.

The existence of spot reduction, exercise-induced local body fat reduction, has been debated for half a century. Although the evidence is equivocal, no study has applied aerobic endurance training closely matching interventions for energy expenditure. Sixteen overweight (BMI: 29.8 ± 3.3(SD) kg m-2 ) males (43 ± 9 years) were randomized to: (1) abdominal endurance exercise (AG), combining treadmill running at 70% HRmax (27 min) with 4 × 4 min (30%-40% maximal strength, 1RM) of torso rotation and abdominal crunches (57 min), 4 days⋅week-1 for 10 weeks; or (2) control group (CG) performing only treadmill running (45 min) at 70% HRmax . Local fat mass was measured by dual-energy x-ray absorptiometry (DEXA), along with 1RM, and pulmonary oxygen uptake (to control energy expenditure during training). Trunk fat mass decreased more (697 g, 3%, p < 0.05) in AG (1170 ± 1093 g, 7%; p < 0.05) than in CG (no change). Total fat mass (AG: 1705 ± 1179 g, 6%; CG: 1134 ± 731 g, 5%; both p < 0.01) and body weight (AG: 1.2 ± 1.2 kg, 1%, p < 0.05; CG: 2.3 ± 0.9 kg, 3%, p < 0.01) decreased similarly in AG/CG. Torso rotation (AG: 32 ± 16 kg, 39%, p < 0.01; CG: no change) and abdominal crunch 1RM (AG: 35 ± 16 kg, 36%, p < 0.01; CG: 13 ± 12 kg, 17%, p < 0.05) increased more (p < 0.05/0.01) in AG than CG. Abdominal endurance exercise utilized more local fat than treadmill running, indicating that spot reduction exists in adult males.

Reciprocal Regulation of Hepatic TGF-β1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure.

Hepatic TGF-β1 levels are increased in obese humans and mice. Hepatic TGF-β1 maintains glucose homeostasis in lean mice and causes glucose and energy dysregulations in obese and diabetic mice. Hepatic TGF-β1 exerts an autocrine effect to promote hepatic gluconeogenesis via cAMP-dependent protein kinase-mediated Foxo1 phosphorylation at serine 273, endocrine effects on brown adipose tissue action, and inguinal white adipose tissue browning (beige fat), causing energy imbalance in obese and insulin-resistant mice. TGF-β1→Foxo1→TGF-β1 looping in hepatocytes plays a critical role in controlling glucose and energy metabolism in health and disease.

1525-P: Ventromedial Hypothalamic Nucleus Subset Stimulates Tissue Thermogenesis via Preoptic Outputs

Changes in energy status ignite neural circuits that maintain body weight by engaging peripheral mechanisms that control energy expenditure; obesity results for when these responses are no longer sufficient. The key neural circuits that stimulate energy expenditure have not yet been established, but previous research has identified several critical sites (e.g. preoptic area (POA) and ventromedial hypothalamus (VMN)) that could be part of an interconnected system that controls tissue thermogenesis, which is essential for body weight control. Activating SF1-cre VMN cells in male diet-induced obese mice reduces body fat by 25% in 72 hours. This function is likely mediated at least in part by release of the peptide pituitary adenylate cyclase-activating polypeptide (PACAP), since knockout of PACAP in the VMN induces obesity at thermoneutrality (30C) and suppresses temperature above both the brown and beige adipose tissue in response to feeding. Because some VMN cells densely project to the POA, we hypothesized that VMN PACAP cells activate tissue thermogenesis via preoptic outputs. We placed temperature-sensing microchips above a traditional brown (interscapular brown adipose tissue (iBAT) and beige (inguinal white adipose tissue (iWAT) adipose tissue in Adcyap1(gene for PACAP)cre mice with DIO-ChR2 in the VMN and fiber optic implants in two major VMN outputs: the POA and the bed nucleus of the stria terminalis (BST). Activating VMN fibers in the POA that contain PACAP in both male and female mice, but not the BST, increased iBAT and iWAT temperature, and the effect was most robust when the mice were fasted. In summary, these data indicate that VMN PACAP connections with the POA is important for the induction of tissue thermogenesis, particularly when feeding conditions change. VMN PACAP, as well as associated signaling targets, are critical components to energy balance by activating adipose tissue mechanisms that stimulate energy expenditure. Disclosure A.J.Elmendorf: Other Relationship; Eli Lilly and Company. C.A.Mahler: Stock/Shareholder; AbbVie Inc., Pfizer Inc., AstraZeneca. B.Lorentz: Research Support; Eli Lilly and Company. J.Flak: Research Support; Eli Lilly and Company. Funding American Diabetes Association (Pathway 17-INI-15 to J.F.); Ralph W. and Grace M. Showalter Research Trust; Indiana University; Indiana Biosciences Research Institute

A robust variable-structure LQI controller for under-actuated systems via flexible online adaptation of performance-index weights.

This article presents flexible online adaptation strategies for the performance-index weights to constitute a variable structure Linear-Quadratic-Integral (LQI) controller for an under-actuated rotary pendulum system. The proposed control procedure undertakes to improve the controller's adaptability, allowing it to flexibly manipulate the control stiffness which aids in efficiently rejecting the bounded exogenous disturbances while preserving the system's closed-loop stability and economizing the overall control energy expenditure. The proposed scheme is realized by augmenting the ubiquitous LQI controller with an innovative online weight adaptation law that adaptively modulates the state-weighting factors of the internal performance index. The weight adaptation law is formulated as a pre-calibrated function of dissipative terms, anti-dissipative terms, and model-reference tracking terms to achieve the desired flexibility in the controller design. The adjusted state weighting factors are used by the Riccati equation to yield the time-varying state-compensator gains.

Discrete optimal quadratic AGC based cost functional minimization for interconnected power systems

The increasing complexity and difficulty of the Automatic generation control (AGC) problem has resulted from the increasing scale of interconnected power networks and changing daily demands. The primary goals of AGC are to control frequency variations at nominal levels and tie-line power variances at planned levels. To effectively deal with AGC control difficulties, this study introduces Discrete Optimal Quadratic Automatic Generation Control (OQAGC). One advantages of this method is the differentiation of quadratic cost function results into linear terms while minimizing control actions and minimizing state deviations. This developed control method leads to a simple and easy discrete control law that can be implemented for both linear and nonlinear systems. For optimizing the controller, this research work utilized an optimum control theorem using Lagrangian multipliers, while the functional minimization technique is used for systematically selecting the state and control weighting matrices in discrete form for N control regions (where N is the number of interconnected power systems). The discrete cost function needs are derived using this technique in terms of area control errors, integral area control errors, and control energy expenditure. Four interconnected power systems were analyzed with/without disturbances and area control errors, each with one thermal, hydro, and gas-generating unit. A two-area multi-source power system with renewable energy in control area 2 is analyzed for the performance of the proposed controller with generation rate constraints (GRCs). The functional minimization technique simplifies and eases the choosing of weighting matrices. Furthermore, the simulation findings suggest that the developed discrete optimum quadratic AGC control-based cost functional minimization approach enhances power system dynamics in terms of stability, steady-state performance, and the closed-loop control system's robustness to input load disturbances. As a result, the newly developed OQAGC approach demonstrates the significance of the discrete LQR controller for N multi-area power systems.

Circulating thrifty microRNA is related to insulin sensitivity, adiposity, and energy metabolism in adults with overweight and obesity: the POUNDS Lost trial

BackgroundMicroRNA 128-1 (miR-128-1) was recently linked to the evolutionary adaptation to famine and identified as a thrifty microRNA that controls energy expenditure, contributing to obesity and impaired glucose metabolism. ObjectivesWe investigated whether circulating miR-128-1-5p and its temporal changes in response to weight-loss diet interventions were related to regulating insulin resistance, adiposity, and energy expenditure in adults with overweight and obesity. We also examined whether habitual physical activity (PA) and different macronutrient intakes modified associations of changes in miR-128-1-5p with improved metabolic outcomes. MethodsThis study included 495 adults who consumed weight-loss diets with different macronutrient intakes. Circulating levels of miR-128-1-5p were assessed at baseline and 6 mo after the interventions. Outcome measurements included changes in insulin resistance HOMA-IR, adiposity, and resting energy expenditure. ResultsWe observed significant relations between circulating miR-128-1-5p and the positive selection signals at the 2q21.3 locus assessed by the single nucleotide polymorphisms rs1446585 and rs4988235. Higher miR-128-1-5p levels were associated with greater HOMA-IR (β per 1 SD: 0.08 [SE 0.03]; P = 0.009), waist circumference (β, 1.16 [0.55]; P = 0.036), whole-body total % fat mass (β, 0.75 [0.30]; P = 0.013), and REE (β, 23 [11]; P = 0.037). In addition, higher miR-128-1-5p level was related to lower total PA index (β, −0.23 [0.07]; P = 0.001) and interacted with PA (Pinteraction < 0.05) on changes in HOMA-IR and adiposity. We found that greater increases in miR-128-1-5p levels after the interventions were associated with lesser improvements in HOMA-IR and adiposity in participants with no change/decreases in PA. Furthermore, we found that dietary fat (Pinteraction = 0.027) and protein (Pinteraction= 0.055) intakes modified relations between changes in miR-128-1-5p and REE. ConclusionsCirculating thrifty miRNA was linked to regulating body fat, insulin resistance, and energy metabolism. Temporal changes in circulating miR-128-1-5p were associated with better weight-loss outcomes during the interventions; habitual PA and dietary macronutrient intake may modify such relations.This trial was registered at clinicaltrials.gov as NCT00072995.

PMON53 Resistance to weight gain and obesity in mice lacking the IGF-1 receptor in GHRH neurons

Abstract IGF-1 signaling plays a pivotal role in regulating GH production through a negative feedback mechanism at the level of the hypothalamus and pituitary. We created a transgenic mouse model with ablation of the IGF-1R in GHRH-neurons (GIGFRKO) that exhibited normal linear growth, however, when fed a normal chow diet, began to have a sustained decrease in weight gain velocity. This was associated with greater energy expenditure and a lower body fat mass, with no change in caloric intake. The aim of the current study was to determine whether this metabolic phenotype would be sustained with a high fat diet challenge. At 4 weeks of age, the mice were placed on a 45% fat diet for 16 weeks. The GIGFRKO mouse model fed a HFD had normal linear growth, but at 10 weeks of age, both male and female mice began to have a sustained decrease in weight gain velocity compared to their age and sex-matched controls. The metabolic assessment demonstrated that the GIGFRKO transgenic mice had higher O2 consumption, lower CO2 production, a reduction in body fat mass, an elevation in energy expenditure, and improved glucose tolerance compared to the control mice on HFD. This was not associated with changes in food intake or activity and was present in males and females. In conclusion, the GIGFRKO transgenic mice are resistant to diet-induced obesity due to the critical role of the GHRH-GH axis in controlling energy expenditure and fat metabolism. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Computational study of potential inhibitors for fat mass and obesity-associated protein from seaweed and plant compounds.

BackgroundOver the past three decades, with substantial changes in lifestyle, the tendency to gain weight has increased, which is resulting in significant consequences affecting an individual’s well-being. The fat mass and obesity-associated (FTO) gene is involved in food intake and energy expenditure and plays a crucial role in regulating homeostasis and controlling energy expenditure by hindering signals that generate from the brain. Edible seaweeds have been shown to enhance satiety owing to their health benefits.MethodsExtensive screening of plant-derived anti-obesity compounds and seaweed compounds was conducted and validated for ADME properties and toxicity prediction. Further, the top ranked compounds were docked against the FTO protein to identify potential inhibitors and were subjected to molecular dynamic simulation studies to understand the binding stability of ligand protein complex. Finally, MM/PBSA studies were performed to calculate the binding free energy of the protein-ligand complexes.ResultsThrough the virtual screening of 1,210 compounds, 443 compounds showed good docking scores less than −7.00 kcal/mol. Drug likeness screenings of 443 compounds showed that only 369 compounds were in accordance with these properties. Further toxicity prediction resulted in 30 non-toxic compounds. Molecular docking studies revealed four top ranked marine compounds. Finally, RL074 (2-hydroxyluzofuranone B) and RL442 (10-acetoxyangasiol) from marine red alga Laurencia sp showed good stability from molecular dynamic simulation studies. MM/PBSA results revealed that BT012 (24ε-hydroperoxy-6β-hydroxy-24-ethylcholesta-4,-28(29)-dien-3-one), an oxygenated fucosterol from brown alga Turbinaria conoides, possessed higher binding energy. Hence, with all the data obtained it could be concluded that three seaweed compounds, BT012, RL074 and RL442, may act as a potential anti-obesity lead compound in targeting FTO.

Knockdown of Endogenous Nucb2/Nesfatin-1 in the PVN Leads to Obese-Like Phenotype and Abolishes the Metformin- and Stress-Induced Thermogenic Response in Rats.

Nesfatin-1, the cleavage product of nucleobindin-2, is an anorexigenic peptide and major regulator of energy homeostasis. Beyond reducing food intake and increasing energy expenditure, it is also involved in regulating the stress response. Interaction of nucleobindin-2/nesfatin-1 and glucose homeostasis has been observed and recent findings suggest a link between the action of the antidiabetic drug metformin and the nesfatinergic system. Hence, this study aimed to clarify the role of nucleobindin-2/nesfatin-1 in the paraventricular nucleus of the hypothalamus in energy homeostasis as well as its involvement in stress- and metformin-mediated changes in energy expenditure. Knockdown of nucleobindin-2/nesfatin-1 in male Wistar rats led to significantly increased food intake, body weight, and reduced energy expenditure compared to controls. Nucleobindin-2/nesfatin-1 knockdown animals developed an obese-like phenotype represented by significantly increased fat mass and overall increase of circulating lipids. Concomitantly, expression of nucleobindin-2 and melanocortin receptor type 3 and 4 mRNA in the paraventricular nucleus was decreased indicating successful knockdown and impairment at the level of the melanocortin system. Additionally, stress induced activation of interscapular brown adipose tissue was significantly decreased in nucleobindin-2/nesfatin-1 knockdown animals and accompanied by lower adrenal weight. Finally, intracerebroventricular administration of metformin significantly increased energy expenditure in controls and this effect was absent in nucleobindin-2/nesfatin-1 knockdown animals. Overall, we clarified the crucial role of nucleobindin-2/nesfatin-1 in the paraventricular nucleus of the hypothalamus in the regulation of energy homeostasis. The nesfatinergic system was further identified as important mediator in stress- and metformin-induced thermogenesis.

Design of Fixed-Sequence Planar 5R Symmetrical Parallel Manipulators

Designing manipulation systems where the gripper has predetermined initial and final positions is an important practical consideration in modern robotics; in other words, achieving the objective of moving the payload along a non-imposed trajectory between two given positions, with the ability to change these positions periodically. One solution to the problem is to create a one-degree-of-freedom system with adjustable parts. This approach is considered optimal in terms of its simplified control and minimum energy expenditure. The merit of the solution is that manipulation systems of this type with cyclic control have only one actuator; the simple design and the control system improve the operational reliability of the mechanical system while greatly reducing the cost of it. The present work proposes a new design concept for a planar 5R symmetrical parallel manipulator. The aim of the proposed design principle is that the two input links of the manipulator are interconnected. The last one is determined in such a way that the initial and final positions of the gripper are ensured. Thus, the obtained mechanical system, having only one actuator, ensures the movement of the gripper between predetermined initial and final positions. The dynamics of the manipulation system, in particular the balancing of shaking force and shaking moment to reduce vibration in the frame, are considered in addition to the purely kinetic aspects. Numerical simulations are used to illustrate the proposed design concept.

DNAJC6 Gene Depressed Adipogenesis and Insulin Signaling in 3T3-L1 Cells

ObjectivesResting metabolic rate (RMR) accounts for 60–70% of total daily energy expenditure, and it is essential for establishing energy balance to prevent obesity. In a previous Genome-Wide Association Study (GWAS) for childhood obesity, we found the DNAJC6 gene as one of the genes that affected obesity prevalence to control energy expenditure with RMR. Since the mechanisms of the DNAJC6 gene on obesity are not clear, we performed adipogenesis, inflammatory adipokines, insulin resistance, and mitochondrial function to confirm dysfunction of energy balance using DNAJC6-overexpressed 3T3-L1 cells.MethodsCompared to the control, the gene expression in DNAJC6-overexpressed was confirmed by MTT, RT-PCR, and western blotting. Adipogenesis and lipolysis were confirmed by ORO staining, the levels of triglyceride & free glycerol in medium, and western blotting for protein expression related to adipokines, insulin resistance, and mitochondrial function.Results DNAJC6-overexpressed significantly depressed adipogenesis (PPARγ, C/EBPα, aP2) and adipokines (LEPR, adiponectin, leptin) compared to the control, and it sequentially inhibited the insulin-GLUT4 signal factors (insulin receptor β, IRS-1, Akt (T308), AS160, GLUT4). As a result of ORO staining, it significantly inhibited adipocyte formation compared to the control. The levels of triglyceride & free glycerol in the medium were gradually increased in the control group, but not in DNAJC6-overexpressed, and DNAJC6-overexpressed inhibited lipolysis factor (HSL). UCP1, a mitochondrial thermogenesis marker induced by PGC1α, was suppressed in both groups.ConclusionsWe found that when DNAJC6 was overexpressed in 3T3-L1 cells, lipid synthesis and degradation were inhibited. Moreover, the insulin signal from IRS to Akt, AS160, and GLUT4 was sequentially suppressed in DNAJC6-overexpressed, thereby inhibiting intracellular glucose influx. In addition, we found that mitochondrial thermogenesis was inhibited by DNAJC6-overexpressed. Based on these findings, further studies are needed to understand the mechanism of how adipocytes overexpressing the DNAJC6 gene interact with other organs to use energy.Funding SourcesThis work was supported by the National Research Foundation of Korea grant funded by the Korea Government (MSIT;2019R1A2C1008434).

Melanocortin MC4R receptor is required for energy expenditure but not blood pressure effects of angiotensin II within the mouse brain.

The brain renin-angiotensin system (RAS) is implicated in control of blood pressure (BP), fluid intake, and energy expenditure (EE). Angiotensin II (ANG II) within the arcuate nucleus of the hypothalamus contributes to control of resting metabolic rate (RMR) and thereby EE through its actions on Agouti-related peptide (AgRP) neurons, which also contribute to EE control by leptin. First, we determined that although leptin stimulates EE in control littermates, mice with transgenic activation of the brain RAS (sRA) exhibit increased EE and leptin has no additive effect to exaggerate EE in these mice. These findings led us to hypothesize that leptin and ANG II in the brain stimulate EE through a shared mechanism. Because AgRP signaling to the melanocortin MC4R receptor contributes to the metabolic effects of leptin, we performed a series of studies examining RMR, fluid intake, and BP responses to ANG II in mice rendered deficient for expression of MC4R via a transcriptional block (Mc4r-TB). These mice were resistant to stimulation of RMR in response to activation of the endogenous brain RAS via chronic deoxycorticosterone acetate (DOCA)-salt treatment, whereas fluid and electrolyte effects remained intact. These mice were also resistant to stimulation of RMR via acute intracerebroventricular (ICV) injection of ANG II, whereas BP responses to ICV ANG II remained intact. Collectively, these data demonstrate that the effects of ANG II within the brain to control RMR and EE are dependent on MC4R signaling, whereas fluid homeostasis and BP responses are independent of MC4R signaling.

Abstract MP30: Circulating MicroRNA-128-1 And Changes In Energy Metabolism And Insulin Sensitivity In Response To Weight Loss Diet Interventions: The Pounds Lost Trial

Background: MicroRNA (miRNAs) are short non-coding RNAs that play important roles in regulating gene expression. Recently, miR-128-1 was identified as a potential thrifty miRNA that controls energy expenditure, contributing to obesity and metabolic diseases. miR-128-1 is located at the locus harboring the lactase ( LCT ) gene, a hallmark gene of the positive selection and evolutionary adaptation to famine by promoting energy storage. Hypothesis: We investigated whether circulating thrifty miR-128-1 was associated with insulin resistance, adiposity, and energy expenditure among adults with overweight and obesity and tested whether miR-128-1 was associated with changes in these metabolic conditions after low-calorie weight-loss diet interventions. Methods: We included 495 participants from the POUNDS Lost trial with available data on circulating miR-128-1-5p measured at baseline and 6 months after the intervention. The LCT genotype rs4988235, which is responsible for lactase persistence in Europeans, was assessed to analyze the relationship between miR-128-1 and the positive selection at this locus. Outcome measurements included adiposity (weight, waist circumference [WC], and body composition), insulin resistance (HOMA-IR), and energy metabolism. Habitual physical activity was assessed by the Baecke questionnaires; total, leisure time, sport, work index were calculated. Results: The LCT rs4988235 (A) allele was associated with higher levels of miR-128-1 ( p =0.04). Pre-intervention miR-128-1 was significantly and positively associated with HOMA-IR ( p =0.009), insulin ( p =0.008), BMI ( p =0.0002), WC ( p =0.036), and whole-body total % fat mass ( p =0.013), and energy metabolism (resting energy expenditure, oxygen consumption, and carbon dioxide production; p &lt;0.05 for all). Also, we found that higher miR-128-1 was related to lower total physical activity index ( p =0.001) and subscales (leisure index ( p =0.007) and sport index ( p =0.02)). We found significant interactions between miR-128-1 and physical activity on changes in adiposity and insulin resistance at 6 months after the interventions ( P interaction =0.03 for weight; P interaction =0.004 for WC; and P interaction =0.01 for HOMA-IR). Participants with lower levels of physical activity and higher miR-128-1 at baseline responded better to the intervention to improve HOMA-IR at 6 months. There were also significant interactions between changes in miR-128-1 and changes in physical activity on changes in HOMA-IR and energy expenditure. Conclusions: Elevated levels of circulating miR-128-1 were associated with greater adiposity and insulin resistance in adults with overweight and obesity. The thrifty miR-128-1 interacted with physical activity on changes in energy metabolism and insulin sensitivity in response to weight-loss diet interventions.

Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity.

Hypothalamus is a brain region that controls food intake and energy expenditure while sensing signals that convey information about energy status. Within the hypothalamus, molecularly and functionally distinct neurons work in concert under physiological conditions. However, under pathological conditions such as in diet-induced obesity (DIO) model, these neurons show dysfunctional firing patterns and distorted regulation by neurotransmitters and neurohormones. Concurrently, resident glial cells including astrocytes dramatically transform into reactive states. In particular, it has been reported that reactive astrogliosis is observed in the hypothalamus, along with various neuroinflammatory signals. However, how the reactive astrocytes control and modulate DIO by influencing neighboring neurons is not well understood. Recently, new lines of evidence have emerged indicating that these reactive astrocytes directly contribute to the pathology of obesity by synthesizing and tonically releasing the major inhibitory transmitter GABA. The released GABA strongly inhibits the neighboring neurons that control energy expenditure. These surprising findings shed light on the interplay between reactive astrocytes and neighboring neurons in the hypothalamus. This review summarizes recent discoveries related to the functions of hypothalamic reactive astrocytes in obesity and raises new potential therapeutic targets against obesity.

Model‐free incremental adaptive dynamic programming based approximate robust optimal regulation

AbstractThis article presents a new formulation for model‐free robust optimal regulation of continuous‐time nonlinear systems. The proposed reinforcement learning based approach, referred to as incremental adaptive dynamic programming (IADP), utilizes measured input‐state data to allow the design of the approximate optimal incremental control strategy, stabilizing the controlled system incrementally under model uncertainties, environmental disturbances, and input saturation. By leveraging the time delay estimation (TDE) technique, we first use sensor data to reduce the requirement of a complete dynamics, where input‐state data is adopted to construct an incremental dynamics which reflects the system evolution in an incremental form. Then, the resulting incremental dynamics serves to design the approximate optimal incremental control strategy based on adaptive dynamic programming, which is implemented as a simplified single critic structure to get the approximate solution to the value function of the Hamilton–Jacobi–Bellman equation. Furthermore, for the critic neural network, experience data are used to design an off‐policy weight update law with guaranteed weight convergence. Rather importantly, we incorporate a TDE error bound related term into the cost function, whereby the unintentionally introduced TDE error is attenuated during the optimization process. The proofs of system stability and weight convergence are provided. Numerical simulations are conducted to validate the effectiveness and superiority of our proposed IADP, especially regarding the reduced control energy expenditure and the enhanced robustness.