Central Regulation Of Energy Homeostasis Research Articles

Thyroid Hormone Clearance in the Paraventricular Nucleus of Male Mice Regulates Lean Mass and Physical Activity

Introduction: The actions of thyroid hormones (THs) in the central nervous system are relevant to food intake and energy expenditure. TH receptors exhibit high expression in brain areas modulating energy balance, including the arcuate, paraventricular (PVN), supraoptic, and ventromedial (VMH) hypothalamic nuclei. Methods: To examine the role of THs in the regulation of energy balance via action in specific hypothalamic nuclei of the adult mouse, we performed experiments of conditional inactivation of DIO3, the enzyme responsible for the clearance of THs, in the lateral hypothalamus (LH), and VMH and PVN hypothalamic nuclei. We accomplished DIO3 genetic inactivation via stereotaxic injection of the AAV-cre vector into adult mice homozygous for a “floxed” Dio3 allele. Results: Dio3 inactivation in the LH and VMH of males or females did not result in significant changes in body weight 8 weeks after injection. However, inactivation of Dio3 in the PVN resulted in increased body weight (both fat mass and lean mass) and locomotor activity, and decreased hypothalamic Mc4r expression in male, but not female mice. However, PNV-specific Dio3 KO did not cause hyperphagia. Conclusion: These results suggest local TH action influences MC4R signaling and possibly other PVN-associated circuitries, with consequences for body composition and energy balance endpoints, but not for orexigenic pathways. They also support a regulatory role for PVN Dio3 in the central regulation of energy homeostasis in adult life.

The crosstalk between Toll and AMPK signaling pathways mediates growth inhibition of Eriocheir sinensis under deltamethrin stress

Hepatopancreatic necrosis disease (HPND) broke out in 2015 in the Eriocheir sinensis aquaculture region of Xinghua, Jiangsu Province; however, the specific cause of HPND remains unclear. A correlation was found between HPND outbreak and the use of deltamethrin by farmers. In this study, E. sinensis specimens developed the clinical symptoms of HPND after 93 days of deltamethrin stress. The growth of E. sinensis with HPND was inhibited. Adenosine monophosphate-activated protein kinase (AMPK) is a central regulator of energy homeostasis, and its expression was up-regulated in the intestine of E. sinensis with HPND. Growth inhibitory genes (EsCabut, Es4E-BP, and EsCG6770) were also up-regulated in the intestine of E. sinensis with HPND. The expression levels of EsCabut, Es4E-BP, and EsCG6770 decreased after EsAMPK knockdown. Therefore, AMPK mediated the growth inhibition of E. sinensis with HPND. Further analysis indicated the presence of a crosstalk between the Toll and AMPK signaling pathways in E. sinensis with HPND. Multiple genes in the Toll signaling pathway were upregulated in E. sinensis under 93 days of deltamethrin stress. EsAMPK and its regulated growth inhibition genes were down-regulated after the knockdown of genes in the Toll pathway. In summary, the crosstalk between the Toll and AMPK signaling pathways mediates the growth inhibition of E. sinensis under deltamethrin stress.

Neuronal primary cilia integrate peripheral signals with metabolic drives.

Neuronal primary cilia have recently emerged as important contributors to the central regulation of energy homeostasis. As non-motile, microtubule-based organelles, primary cilia serve as signaling antennae for metabolic status. The impairment of ciliary structure or function can produce ciliopathies for which obesity is a hallmark phenotype and global ablation of cilia induces non-syndromic adiposity in mouse models. This organelle is not only a hub for metabolic signaling, but also for catecholamine neuromodulation that shapes neuronal circuitry in response to sensory input. The objective of this review is to highlight current research investigating the mechanisms of primary cilium-regulated metabolic drives for maintaining energy homeostasis.

Hormonal Gut-Brain Signaling for the Treatment of Obesity.

The brain, particularly the hypothalamus and brainstem, monitors and integrates circulating metabolic signals, including gut hormones. Gut-brain communication is also mediated by the vagus nerve, which transmits various gut-derived signals. Recent advances in our understanding of molecular gut-brain communication promote the development of next-generation anti-obesity medications that can safely achieve substantial and lasting weight loss comparable to metabolic surgery. Herein, we comprehensively review the current knowledge about the central regulation of energy homeostasis, gut hormones involved in the regulation of food intake, and clinical data on how these hormones have been applied to the development of anti-obesity drugs. Insight into and understanding of the gut-brain axis may provide new therapeutic perspectives for the treatment of obesity and diabetes.

Deletion of Androgen Receptor in LepRb Cells Improves Estrous Cycles in Prenatally Androgenized Mice.

Androgens are steroid hormones crucial for sexual differentiation of the brain and reproductive function. In excess, however, androgens may decrease fertility as observed in polycystic ovary syndrome, a common endocrine disorder characterized by oligo/anovulation and/or polycystic ovaries. Hyperandrogenism may also disrupt energy homeostasis, inducing higher central adiposity, insulin resistance, and glucose intolerance, which may exacerbate reproductive dysfunction. Androgens bind to androgen receptors (ARs), which are expressed in many reproductive and metabolic tissues, including brain sites that regulate the hypothalamo-pituitary-gonadal axis and energy homeostasis. The neuronal populations affected by androgen excess, however, have not been defined. We and others have shown that, in mice, AR is highly expressed in leptin receptor (LepRb) neurons, particularly in the arcuate (ARH) and the ventral premammillary nuclei (PMv). Here, we assessed if LepRb neurons, which are critical in the central regulation of energy homeostasis and exert permissive actions on puberty and fertility, have a role in the pathogenesis of female hyperandrogenism. Prenatally androgenized (PNA) mice lacking AR in LepRb cells (LepRbΔAR) show no changes in body mass, body composition, glucose homeostasis, or sexual maturation. They do show, however, a remarkable improvement of estrous cycles combined with normalization of ovary morphology compared to PNA controls. Our findings indicate that the prenatal androgenization effects on adult reproductive physiology (ie, anestrus and anovulation) are mediated by a subpopulation of LepRb neurons directly sensitive to androgens. They also suggest that the effects of hyperandrogenism on sexual maturation and reproductive function in adult females are controlled by distinct neural circuits.

Gap junctions regulate the activity of AgRP neurons and diet-induced obesity in male mice.

Recent studies indicated an important role of connexins, gap junction proteins, in the regulation of metabolism. However, most of these studies focused on the glial expression of connexins, whereas the actions of connexins in neurons are still poorly investigated. Thus, the present study had the objective to investigate the possible involvement of gap junctions, and in particular connexin 43 (CX43), for the central regulation of energy homeostasis. Initially, we demonstrated that hypothalamic CX43 expression was suppressed in fasted mice. Using whole-cell patch-clamp recordings, we showed that pharmacological blockade of gap junctions induced hyperpolarization and decreased the frequency of action potentials in 50-70% of agouti-related protein (AgRP)-expressing neurons, depending on the blocker used (carbenoxolone disodium, TAT-Gap19 or Gap 26). When recordings were performed with a biocytin-filled pipette, this intercellular tracer was detected in surrounding cells. Then, an AgRP-specific CX43 knockout (AgRPΔCX43) mouse was generated. AgRPΔCX43 mice exhibited no differences in body weight, adiposity, food intake, energy expenditure and glucose homeostasis. Metabolic responses to 24 h fasting or during refeeding were also not altered in AgRPΔCX43 mice. However, AgRPΔCX43 male, but not female mice, exhibited a partial protection against high-fat diet-induced obesity, even though no significant changes in energy intake or expenditure were detected. In summary, our findings indicate that gap junctions regulate the activity of AgRP neurons, and AgRP-specific CX43 ablation is sufficient to mildly prevent diet-induced obesity specifically in males.

Neuroendocrine microRNAs linked to energy homeostasis: future therapeutic potential.

The brain orchestrates whole-body metabolism through an intricate system involving interneuronal crosstalk and communication. Specifically, a key player in this complex circuitry is the hypothalamus that controls feeding behaviour, energy expenditure, body weight and metabolism, whereby hypothalamic neurons sense and respond to circulating hormones, nutrients, and chemicals. Dysregulation of these neurons contributes to the development of metabolic disorders, such as obesity and type 2 diabetes. The involvement of hypothalamic microRNAs, post-transcriptional regulators of gene expression, in the central regulation of energy homeostasis has become increasingly apparent, although not completely delineated. This review summarizes current evidence demonstrating the regulation of feeding-related neuropeptides by brain-derived microRNAs as well as the regulation of specific miRNAs by nutrients and other peripheral signals. Moreover, the involvement of microRNAs in the central nervous system control of insulin, leptin, and estrogen signal transduction is examined. Finally, the therapeutic and diagnostic potential of microRNAs for metabolic disorders will be discussed andthe regulation of brain-derived microRNAs by nutrients and other peripheral signals is considered. Demonstrating a critical role of microRNAs in hypothalamic regulation of energy homeostasis is an innovative route to uncover novel biomarkers and therapeutic candidates for metabolic disorders.

TRIM67 Deficiency Exacerbates Hypothalamic Inflammation and Fat Accumulation in Obese Mice.

Obesity has achieved the appearance of a global epidemic and is a serious cause for concern. The hypothalamus, as the central regulator of energy homeostasis, plays a critical role in regulating food intake and energy expenditure. In this study, we show that TRIM67 in the hypothalamus was responsive to body-energy homeostasis whilst a deficiency of TRIM67 exacerbated metabolic disorders in high-fat-diet-induced obese mice. We found exacerbated neuroinflammation and apoptosis in the hypothalamus of obese TRIM67 KO mice. We also found reduced BDNF in the hypothalamus, which affected the fat sympathetic nervous system innervation and contributed to lipid accumulation in adipose tissue under high-fat-diet exposure. In this study, we reveal potential implications between TRIM67 and the hypothalamic function responding to energy overuptake as well as a consideration for the therapeutic diagnosis of obesity.

Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator.

The AMP-activated protein kinase (AMPK) αβγ heterotrimer is a primary cellular energy sensor and central regulator of energy homeostasis. Activating skeletal muscle AMPK with small molecule drugs improves glucose uptake and provides an opportunity for new strategies to treat type 2 diabetes and insulin resistance, with recent genetic and pharmacological studies indicating the α2β2γ1 isoform combination as the heterotrimer complex primarily responsible. With the goal of developing α2β2-specific activators, here we perform structure/function analysis of the 2-hydroxybiphenyl group of SC4, an activator with tendency for α2-selectivity that is also capable of potently activating β2 complexes. Substitution of the LHS 2-hydroxyphenyl group with polar-substituted cyclohexene-based probes resulted in two AMPK agonists, MSG010 and MSG011, which did not display α2-selectivity when screened against a panel of AMPK complexes. By radiolabel kinase assay, MSG010 and MSG011 activated α2β2γ1 AMPK with one order of magnitude greater potency than the pan AMPK activator MK-8722. A crystal structure of MSG011 complexed to AMPK α2β1γ1 revealed a similar binding mode to SC4 and the potential importance of an interaction between the SC4 2-hydroxyl group and α2-Lys31 for directing α2-selectivity. MSG011 induced robust AMPK signalling in mouse primary hepatocytes and commonly used cell lines, and in most cases this occurred in the absence of changes in phosphorylation of the kinase activation loop residue α-Thr172, a classical marker of AMP-induced AMPK activity. These findings will guide future design of α2β2-selective AMPK activators, that we hypothesise may avoid off-target complications associated with indiscriminate activation of AMPK throughout the body.

Tumor protein D52 (TPD52) affects cancer cell metabolism by negatively regulating AMPK.

The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, with deregulation leading to cancer and other diseases. However, how this pathway is dysregulated in cancer has not been well clarified. Using a tandem affinity purification/mass-spec technique and biochemical analyses, we identified tumor protein D52 (TPD52) as an AMPKα-interacting molecule. To explore the biological effects of TPD52 in cancers, we conducted biochemical and metabolic assays in vitro and in vivo with cancer cells and TPD52 transgenic mice. Finally, we assessed the clinical significance of TPD52 expression in breast cancer patients using bioinformatics techniques. TPD52, initially identified to be overexpressed in many human cancers, was found to form a stable complex with AMPK in cancer cells. TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activity in vitro and in vivo. In TPD52 transgenic mice, overexpression of TPD52 leads to AMPK inhibition and multiple metabolic defects. Clinically, high TPD52 expression predicts poor survival of breast cancer patients. The findings revealed that TPD52 is a novel regulator of energy stress-induced AMPK activation and cell metabolism. These results shed new light on AMPK regulation and understanding of the etiology of cancers with TPD52 overexpression.

The PACAP Paradox: Dynamic and Surprisingly Pleiotropic Actions in the Central Regulation of Energy Homeostasis.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a pleiotropic neuropeptide, is widely distributed throughout the body. The abundance of PACAP expression in the central and peripheral nervous systems, and years of accompanying experimental evidence, indicates that PACAP plays crucial roles in diverse biological processes ranging from autonomic regulation to neuroprotection. In addition, PACAP is also abundantly expressed in the hypothalamic areas like the ventromedial and arcuate nuclei (VMN and ARC, respectively), as well as other brain regions such as the nucleus accumbens (NAc), bed nucleus of stria terminalis (BNST), and ventral tegmental area (VTA) – suggesting that PACAP is capable of regulating energy homeostasis via both the homeostatic and hedonic energy balance circuitries. The evidence gathered over the years has increased our appreciation for its function in controlling energy balance. Therefore, this review aims to further probe how the pleiotropic actions of PACAP in regulating energy homeostasis is influenced by sex and dynamic changes in energy status. We start with a general overview of energy homeostasis, and then introduce the integral components of the homeostatic and hedonic energy balance circuitries. Next, we discuss sex differences inherent to the regulation of energy homeostasis via these two circuitries, as well as the activational effects of sex steroid hormones that bring about these intrinsic disparities between males and females. Finally, we explore the multifaceted role of PACAP in regulating homeostatic and hedonic feeding through its actions in regions like the NAc, BNST, and in particular the ARC, VMN and VTA that occur in sex- and energy status-dependent ways.

The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis.

Chemerin is an adipokine involved in inflammation, adipogenesis, angiogenesis and energy metabolism, and has been hypothesized as a link between obesity and type II diabetes. In humans affected by obesity, chemerin gene expression in peripheral tissues and circulating levels are elevated. In mice, plasma levels of chemerin are upregulated by high-fat feeding and gain and loss of function studies show an association of chemerin with body weight, food intake and glucose homeostasis. Therefore, chemerin is an important blood-borne mediator that, amongst its other functions, controls appetite and body weight. Almost all studies of chemerin to date have focused on its release from adipose tissue and its effects on peripheral tissues with the central effects largely overlooked. To demonstrate a central role of chemerin, we manipulated chemerin signaling in the hypothalamus, a brain region associated with appetite regulation, using pharmacological and genetic manipulation approaches. Firstly, the selective chemerin receptor CMKLR1 antagonist α-NETA was administered i.c.v. to rats to test for an acute physiological effect. Secondly, we designed a short-hairpin-RNA (shRNA) lentivirus construct targeting expression of CMKLR1. This shRNA construct, or a control construct was injected bilaterally into the arcuate nucleus of male Sprague Dawley rats on high-fat diet (45%). After surgery, rats were maintained on high-fat diet for 2 weeks and then switched to chow diet for a further 2 weeks. We found a significant weight loss acutely and inhibition of weight gain chronically. This difference became apparent after diet switch in arcuate nucleus-CMKLR1 knockdown rats. This was not accompanied by a difference in blood glucose levels. Interestingly, appetite-regulating neuropeptides remained unaltered, however, we found a significant reduction of the inflammatory marker TNF-α suggesting reduced expression of CMKLR1 protects from high-fat diet induced neuroinflammation. In white and brown adipose tissue, mRNA expression of chemerin, its receptors and markers of adipogenesis, lipogenesis and brown adipocyte activation remained unchanged confirming that the effects are driven by the brain. Our behavioral analyses suggest that knockdown of CMKLR1 had an impact on object recognition. Our data demonstrate that CMKLR1 is functionally important for the central effects of chemerin on body weight regulation and neuroinflammation.

Conditional gene targeting using UCP1-Cre mice directly targets the central nervous system beyond thermogenic adipose tissues

ObjectiveUncoupling protein 1 (UCP1) is a mitochondrial protein critical for adaptive thermogenesis in adipose tissues, and it is typically believed to be restricted to thermogenic adipose tissues. UCP1-Cre transgenic mice are utilized in numerous studies to provide “brown adipose-specific” conditional gene targeting. Here, we examined the distribution of Cre and UCP1 throughout the body in UCP1-Cre reporter mice. MethodsUCP1-Cre mice crossed to Ai14-tdTomato and Ai9-tdTomato reporter mice were used to explore the tissue distribution of Cre recombinase and Ucp1 mRNA in various tissues. UCP1-Cre mice were independently infected with either a Cre-dependent PHP.eB-tdTomato virus or a Cre-dependent AAV-tdTomato virus to determine whether and where UCP1 is actively expressed in the adult central nervous system. In situ analysis of the deposited single cell RNA sequencing data was used to evaluate Ucp1 expression in the hypothalamus. ResultsAs expected, Ucp1 expression was detected in both brown and inguinal adipose tissues. Ucp1 expression was also detected in the kidney, adrenal glands, thymus, and hypothalamus. Consistent with detectable Ucp1 expression, tdTomato expression was also observed in brown adipose tissue, inguinal white adipose tissue, kidney, adrenal glands, and hypothalamus of both male and female UCP1-Cre; Ai14-tdTomato and UCP1-Cre; Ai9-tdTomato mice by fluorescent imaging and qPCR. Critically, expression of tdTomato, and thus UCP1, within the central nervous system was observed in regions of the brain critical for the regulation of energy homeostasis, including the ventromedial hypothalamus (VMH). ConclusionsTdTomato expression in UCP1-Cre; tdTomato mice is not restricted to thermogenic adipose tissues. TdTomato was also expressed in the kidneys, adrenal glands, and throughout the brain, including brain regions and cell types that are critical for multiple aspects of central regulation of energy homeostasis. Collectively, these data have important implications for the utility of UCP1-Cre mice as genetic tools to investigate gene function specifically in brown adipose tissue.

The Chemerin-CMKLR1 Axis is Functionally Important for Central Regulation of Energy Homeostasis

The Chemerin-CMKLR1 Axis is Functionally Important for Central Regulation of Energy Homeostasis

Nuclear UHRF1 is a gate-keeper of cellular AMPK activity and function.

The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis. Although much has been learned on how low energy status and glucose starvation activate AMPK, how AMPK activity is properly controlled in vivo is still poorly understood. Here we report that UHRF1, an epigenetic regulator highly expressed in proliferating and cancer cells, interacts with AMPK and serves to suppress AMPK activity under both basal and stressed conditions. As a nuclear protein, UHRF1 promotes AMPK nuclear retention and strongly suppresses nuclear AMPK activity toward substrates H2B and EZH2. Importantly, we demonstrate that UHRF1 also robustly inhibits AMPK activity in the cytoplasm compartment, most likely as a consequence of AMPK nucleocytoplasmic shuttling. Mechanistically, we found that UHRF1 has no obvious effect on AMPK activation by upstream kinases LKB1 and CAMKK2 but inhibits AMPK activity by acting as a bridging factor targeting phosphatase PP2A to dephosphorylate AMPK. Hepatic overexpression of UHRF1 showed profound effects on glucose and lipid metabolism in wild-type mice but not in those with the liver-specific knockout of AMPKα1/α2, whereas knockdown of UHRF1 in adipose tissue led to AMPK activation and reduced sizes of adipocytes and lipogenic activity, highlighting the physiological significance of this regulation in glucose and lipid metabolism. Thus, our study identifies UHRF1 as a novel AMPK gate-keeper with critical roles in cellular metabolism.

The influence of thyroid state on hypothalamic AMP-activated protein kinase pathways in broilers

To investigate whether there are important interactions in play in broilers between thyroid hormones and the central regulation of energy homeostasis through AMP-activated protein kinase (AMPK), we induced a functional hyperthyroid and hypothyroid state in broiler chicks, and quantified systemic and hypothalamic AMPK related gene expression and related protein. Thyroid state was manipulated through dietary supplementation of triiodothyronine (T3) or methimazole (MMI) for 7 days. A hypothalamic AMPK suppressor, 0.1% α-lipoic acid (α-LA) was used to assess the effects of the T3 and MMI feed formulations on the AMPK pathways. Feed intake and body weight were reduced in both hypothyroid and hyperthyroid conditions. In hyperthyroid conditions (T3 supplementation) expression of the AMPKα1 subunit increased, while in hypothyroid conditions (MMI supplementation) active phosphorylated AMPK levels in the hypothalamus dropped, but gene expression of the AMPKα1 and α2 subunit increased. For FAS and ACC (involved in fatty acid metabolism), and CRH, TRH and CNR1 (anorexigenic neuropeptides stimulating energy expenditure) there were indications that their regulation in response to thyroid state might be modulated through AMPK pathways. Our results indicate that the expression of hypothalamic AMPK as well as that of several other genes from AMPK pathways are involved in thyroid-hormone-induced changes in appetite, albeit differently according to thyroid state.

The autophagy protein Becn1 improves insulin sensitivity by promoting adiponectin secretion via exocyst binding.

SUMMARYAutophagy dysregulation is implicated in metabolic diseases, including type 2 diabetes. However, the mechanism by which the autophagy machinery regulates metabolism is largely unknown. Autophagy is generally considered a degradation process via lysosomes. Here, we unveil a metabolically important non-cell-autonomous, non-degradative mechanism regulated by the essential autophagy protein Becn1 in adipose tissue. Upon high-fat diet challenge, autophagy-hyperactive Becn1F121A mice show systemically improved insulin sensitivity and enhanced activation of AMP-activated protein kinase (AMPK), a central regulator of energy homeostasis, via a non-cell-autonomous mechanism mediated by adiponectin, an adipose-derived metabolic hormone. Adipose-specific Becn1F121A expression is sufficient to activate AMPK in non-adipose tissues and improve systemic insulin sensitivity by increasing adiponectin secretion. Further, Becn1 enhances adiponectin secretion by interacting with components of the exocyst complex via the coiled-coil domain. Together, our study demonstrates that Becn1 improves insulin sensitivity by facilitating adiponectin secretion through binding the exocyst in adipose tissue.

The relationship between body height and weight toward blood hemoglobin level in the teen athletes

Background: Performance sports are carried out with high intensity and require excellent physical preparedness. This study aims to determine the relationship between height, weight, and athlete's blood hemoglobin level.Methods: This research was an analytic observational type with a cross-sectional study design among 49 male and female athletes enrolled with the total sampling technique. Data were analyzed with a descriptive test, and normality test, and multiple correlations. A significance value of p ≤ 0.05 and research data was analyzed using software SPSS version 20 for Windows.Results: Most respondents in both genders were normal in BMI (85.72%). However, anemia status tends to be higher in males (23.33%) than females (10.52%). The multiple correlation tests showed a moderate level of correlation with a value of r=0.408. The significance analysis of the value of p=0.015 indicatesthat there is a significant correlation between Height, Weight, and Blood Hemoglobin (Hb) level (p<0.05).Conclusion: There is a significant moderate positive correlation between height and weight to blood hemoglobin level.1.    Eime RM, Harvey JT, Charity MJ, Casey MM, van Uffelen JG, Payne WR. The contribution of sport participation to overall health enhancing physical activity levels in Australia: a population-based study. BMC Public Health. 2015;15:806. 2.    Holecek V, Liska J, Racek J, Rokyta R. The significance of free radicals and antioxidants due to the load induced by sport activity. Cesk Fysiol. 2004;53(2):76-79.3.    Patterson CM, Levin BE. Role of exercise in the central regulation of energy homeostasis and in the prevention of obesity. Neuroendocrinology. 2008;87(2):65-70. 4.    Stanula A, Roczniok R, Gabryś T, Szmatlan-Gabryś U, Maszczyk A, Pietraszewski P. Relations between BMI, body mass and height, and sports competence among participants of the 2010 Winter Olympic Games: does sport metabolic demand differentiate?. Percept Mot Skills. 2013;117(3):837-854. 5.    Maughan R. The athlete's diet: nutritional goals and dietary strategies. Proc Nutr Soc. 2002;61(1):87-96. 6.    Barnes HV. Physical growth and development during puberty. Med Clin North Am. 1975;59(6):1305-1317. 7.    Utkualp N, Ercan I. Anthropometric Measurements Usage in Medical Sciences. Biomed Res Int. 2015;2015:404261.8.    Goodrich JA, Ryan BJ, Byrnes WC. The Influence of Oxygen Saturation on the Relationship Between Hemoglobin Mass and VO 2 max. Sports Med Int Open. 2018;2(4):E98-E104. 9.    Smith DW. The molecular biology of mammalian hemoglobin synthesis. Ann Clin Lab Sci. 1980;10(2):116-122.10. Soliman AT, Sanctis VD, Kalra S. Anemia and Growth. Indian J Endocrinol Metab. 2014;18(Suppl 1):S1-S5.11. Prommer N, Wachsmuth N, Thieme I, Wachsmuth C, Mancera-Soto EM, Hohmann A, et al. Influence of Endurance Training During Childhood on Total Hemoglobin Mass. Front Physiol. 2018;9:251. 12. Bell SG. An introduction to hemoglobin physiology. Neonatal Netw. 1999;18(2):9-15. 13. Namita, Ranjan DP. A Cross-Sectional Study of Association Between Hemoglobin  Level and Body Mass Index Among Adolescent Age Group. Natl J Physiol Pharm Pharmacol. 2019;9(8):746-750.14. Syah MNH, Asna AF. Resiko Gangguan Makandan Kejadian Anemia pada Mahasiswa Putri Program Studi S1 Gizi STIKES Mitra Keluarga. Jurnal Gizi dan Kesehatan. 2018;2(1):1-6.15. Acharya S, Patnaik M, Mishra SP, Panigrahi AK. Correlation of Hemoglobin Versus Body Mass Index and Body Fat in young Adult Female Medical Students. Natl J Physiol Pharm Pharmacol. 2018;8(10):1371-1373.

The Autophagy Protein Becn1 Improves Insulin Sensitivity by Promoting Adiponectin Secretion Via Exocyst Binding

Beclin 1/Becn1 is an essential protein in autophagy, a stress-induced lysosomal degradation pathway. Autophagy dysregulation is implicated in the pathogenesis of metabolic diseases such as type 2 diabetes. However, the mechanism of the autophagy machinery in metabolic regulation is poorly understood. In this study, we discovered a metabolically important secretory function of Becn1 in adipose tissue, which is distinct from its role in degradation. In response to high-fat diet challenge, autophagy-hyperactive Becn1F121A mice, caused by a constitutively active Becn1F121A mutation, show systemically improved insulin sensitivity and enhanced activation of AMP-activated protein kinase (AMPK), a central regulator of energy homeostasis, via a non-cell autonomous mechanism. We further identified that the circulating factor that activates AMPK systemically in Becn1F121A mice is adiponectin, a metabolic hormone secreted from adipocytes. The Becn1-facilitated adiponectin secretion is regulated by upstream autophagy modulators, and is mediated by binding of the coiled-coil domain of Becn1 with subunits of the exocyst complex. In addition, adipose tissue-specific Becn1F121A expression is sufficient to activate liver AMPK and improve systemic insulin sensitivity by increasing adiponectin secretion. Altogether, we demonstrated that Becn1 improves insulin sensitivity by facilitating adiponectin secretion through interacting with the exocyst in adipose tissue. Our study highlights a novel non-cell autonomous, non-degradative, mechanism by which the autophagy machinery regulates metabolism.

A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet

The hypothalamus is the central regulator of energy homeostasis. Hypothalamic neuronal circuits are disrupted upon overfeeding, and play a role in the development of metabolic disorders. While mouse models have been extensively employed for understanding the mechanisms of hypothalamic dysfunction, functional magnetic resonance imaging (fMRI) on hypothalamic nuclei has been challenging. We implemented a robust glucose-induced fMRI paradigm that allows to repeatedly investigate hypothalamic responses to glucose. This approach was used to test the hypothesis that hypothalamic nuclei functioning is impaired in mice exposed to a high-fat and high-sucrose diet (HFHSD) for seven days. The blood oxygen level-dependent (BOLD) fMRI signal was measured from brains of mice under light isoflurane anaesthesia, during which a 2.6 g/kg glucose load was administered. The mouse hypothalamus responded to glucose but not saline administration with a biphasic BOLD fMRI signal reduction. Relative to controls, HFHSD-fed mice showed attenuated or blunted responses in arcuate nucleus, lateral hypothalamus, ventromedial nucleus and dorsomedial nucleus, but not in paraventricular nucleus. In sum, we have developed an fMRI paradigm that is able to determine dysfunction of glucose-sensing neuronal circuits within the mouse hypothalamus in a non-invasive manner.