Endocrine role of bone in the regulation of energy metabolism

AbstractsBone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.

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What fuels the fly: Energy metabolism in Drosophila and its application to the study of obesity and diabetes

Science Advances ◽

10.1126/sciadv.abg4336 ◽

2021 ◽

Vol 7 (24) ◽

pp. eabg4336

Author(s):

Nirmalya Chatterjee ◽

Norbert Perrimon

Keyword(s):

Energy Metabolism ◽

Metabolic Pathways ◽

Energy Demand ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Model System ◽

Environmental Cues ◽

Atp Production ◽

Obesity And Diabetes ◽

Dietary Nutrients

The organs and metabolic pathways involved in energy metabolism, and the process of ATP production from nutrients, are comparable between humans and Drosophila melanogaster. This level of conservation, together with the power of Drosophila genetics, makes the fly a very useful model system to study energy homeostasis. Here, we discuss the major organs involved in energy metabolism in Drosophila and how they metabolize different dietary nutrients to generate adenosine triphosphate. Energy metabolism in these organs is controlled by cell-intrinsic, paracrine, and endocrine signals that are similar between Drosophila and mammals. We describe how these signaling pathways are regulated by several physiological and environmental cues to accommodate tissue-, age-, and environment-specific differences in energy demand. Last, we discuss several genetic and diet-induced fly models of obesity and diabetes that can be leveraged to better understand the molecular basis of these metabolic diseases and thereby promote the development of novel therapies.

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DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

Nature Communications ◽

10.1038/s41467-020-20665-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Haiyan Zhou ◽

Xinyi Peng ◽

Jie Hu ◽

Liwen Wang ◽

Hairong Luo ◽

...

Keyword(s):

T Cells ◽

Adipose Tissue ◽

T Cell ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Whole Body ◽

Brown Adipose ◽

Ifn Γ ◽

Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

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Abstract P247: Gut Microbiota From A Rat Model Of Metabolic Syndrome Lowers Fitness Of High Exercise Capacity Rats (HCR/ Tol ) By Impairing Energy Homeostasis And Increasing Blood Pressure

Hypertension ◽

10.1161/hyp.76.suppl_1.p247 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Guannan Zhou ◽

Tao Yang ◽

Sivarajan Kumarasamy ◽

Bina Joe ◽

Lauren G Koch

Keyword(s):

Blood Pressure ◽

Metabolic Syndrome ◽

Energy Metabolism ◽

Gut Microbiota ◽

Exercise Capacity ◽

Energy Homeostasis ◽

Current Knowledge ◽

Strong Predictor ◽

Whole Body ◽

Acid Oxidation

Introduction: Low exercise capacity is a strong predictor of cardiovascular disease and overall mortality. Previously we have shown that rats artificially selected for low intrinsic exercise capacity (LCR) have reduced longevity and develop features consistent with metabolic syndrome (MetS) compared to high intrinsic exercise capacity rats (HCR). Current knowledge suggests that gut microbiota is an important contributor for host fitness. Thus, we hypothesized that transferring gut microbiota from LCR rats into inbred high capacity runner (HCR /Tol ) rats would increase risk factors for MetS, including high blood pressure (BP), gain in body weight (BW), and altered resting energy metabolism. Methods: Gut microbiota was depleted in male HCR/ Tol rats (4 mo.) by an antibiotic cocktail given orally (50mg/kg of BW/day) for 5 days, followed by weekly fecal microbiota transfer (FMT) from male LCR or HCR rats (13 mo.) to generate HCR/ Tol -LCR FMT (n = 5) or HCR/ Tol -HCR FMT (n = 6) groups. BW was measured every 4 weeks. At week 11, whole body metabolism was measured by indirect calorimetry (Oxymax, Columbus Instruments). Respiratory Exchange Ratio (RER), Energy Expenditure (EE), glucose and fat oxidation were calculated from oxygen consumption and carbon dioxide release (VO 2 and VCO 2 ). At week 12, BP was measured by tail-cuff method (Kent Scientific) and treadmill exercise test was done at week 13. Results: Compared to HCR/ Tol -HCR FMT , HCR/ Tol -LCR FMT showed a significant gain in BW (7.2% vs 1.9%, P<0.05), elevated systolic BP (147 vs 120 mmHg, P<0.0001), diastolic BP (112 vs 91 mmHg, P<0.01), and mean BP (123 vs 100 mmHg, P<0.001). BP changes in HCR/ Tol -LCR FMT associated with 1) increased VO 2 (355 vs 320 ml/hr, P<0.05), 2) elevated VCO 2 (350 vs 298 ml/hr, P<0.01), 3) increased EE (1.8 vs 1.6 kcal/hr, P<0.01), 4) higher RER (0.96 vs 0.91, P<0.001), 5) higher glucose oxidation (1.36 vs 1.12 g/kg/hr, P<0.001) and 6) reduced fatty acid oxidation (0.09 vs 0.15 g/kg/hr, P<0.01) and a 23% lower exercise capacity. Conclusions: Gut microbiota from LCR rats strongly associated with poor health outcomes, notably elevated BP and impaired energy metabolism. These findings suggest that altered energy homeostasis by microbiota is mechanistically linked to host BP regulation within MetS.

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Dimorphic metabolic and endocrine disorders in mice lacking the constitutive androstane receptor

Scientific Reports ◽

10.1038/s41598-019-56570-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Céline Lukowicz ◽

Sandrine Ellero-Simatos ◽

Marion Régnier ◽

Fabiana Oliviero ◽

Frédéric Lasserre ◽

...

Keyword(s):

Energy Metabolism ◽

Hepatic Steatosis ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Constitutive Androstane Receptor ◽

Developed Countries ◽

Health Concern ◽

Endocrine Disorders ◽

Male Mice ◽

Treatment Of Obesity

AbstractMetabolic diseases such as obesity, type II diabetes and hepatic steatosis are a public health concern in developed countries. The metabolic risk is gender‐dependent. The constitutive androstane receptor (CAR), which is at the crossroads between energy metabolism and endocrinology, has recently emerged as a promising therapeutic agent for the treatment of obesity and type 2 diabetes. In this study we sought to determine its role in the dimorphic regulation of energy homeostasis. We tracked male and female WT and CAR deficient (CAR−/−) mice for over a year. During aging, CAR−/− male mice developed hypercortisism, obesity, glucose intolerance, insulin insensitivity, dyslipidemia and hepatic steatosis. Remarkably, the latter modifications were absent, or minor, in female CAR−/− mice. When ovariectomized, CAR−/− female mice developed identical patterns of metabolic disorders as observed in male mice. These results highlight the importance of steroid hormones in the regulation of energy metabolism by CAR. They unveil a sexually dimorphic role of CAR in the maintenance of endocrine and metabolic homeostasis underscoring the importance of considering sex in treatment of metabolic diseases.

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Sleep-wake regulation is altered in leptin-resistant (db/db) genetically obese and diabetic mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00026.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. R2059-R2066 ◽

Cited By ~ 79

Author(s):

A. D. Laposky ◽

M. A. Bradley ◽

D. L. Williams ◽

J. Bass ◽

F. W. Turek

Keyword(s):

Energy Metabolism ◽

Eye Movement ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Sleep Time ◽

Rapid Eye Movement ◽

Sleep Regulation ◽

Compensatory Response ◽

Leptin Signaling ◽

Obesity And Diabetes

Recent epidemiological and clinical studies indicate that the control of sleep-wake states may be an important factor in the regulation of energy metabolism. Leptin is a peripherally synthesized hormone that has critical signaling properties in the brain for the control of long-term energy homeostasis. In this study, we examined the hypothesis that leptin signaling exerts a role in sleep-wake regulation and that leptin may represent an important mechanistic link in the coordination of sleep-wake states and metabolism. Sleep-wake patterns were recorded in a genetic mouse model of obesity and diabetes, the db/db mouse, which harbors a mutation in a particular isoform of the leptin receptor (long form, LRb). We found that db/db mice exhibit a variety of alterations in sleep regulation, including an increase in overall sleep time, a dramatic increase in sleep fragmentation, attenuated diurnal rhythmicity in rapid eye movement sleep and non-rapid eye movement EEG delta power (a measure of sleep homeostatic drive), and a decrease in the compensatory response to acute (i.e., 6 h) sleep deprivation. The db/db mice also generated low amounts of locomotor activity and a reduction in the diurnal rhythm of activity. These results indicate that impaired leptin signaling has deleterious effects on the regulation of sleep amount, sleep architecture, and temporal consolidation of these arousal states. In summary, leptin may represent an important molecular component in the integration of sleep, circadian rhythms, and energy metabolism.

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Free leptin index and thyroid function in male highly trained athletes

Acta Endocrinologica ◽

10.1530/eje-09-0569 ◽

2009 ◽

Vol 161 (6) ◽

pp. 871-876 ◽

Cited By ~ 11

Author(s):

Gianluca Perseghin ◽

Guido Lattuada ◽

Francesca Ragogna ◽

Giampietro Alberti ◽

Antonio La Torre ◽

...

Keyword(s):

Energy Metabolism ◽

Thyroid Function ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Anaerobic Power ◽

Biologically Active ◽

Retinol Binding Protein ◽

Endocrine Function ◽

Whole Body ◽

Retinol Binding Protein 4

ObjectiveExercise training may cause changes in thyroid function. This thyroid response may be due to exercise-induced modulation of energy metabolism but also of the adipocytes endocrine function. In particular, the role of leptin and of circulating soluble leptin receptor (sOB-R) was unexplored. The aim of this study was to assess the relationships between thyroid function, whole body energy metabolism, and adipokines – mainly leptin and its receptor, sOB-R.MethodsWe measured serum TSH, free tri-iodothyronine (FT3), free thyroxine, leptin, and sOB-R and assessed energy homeostasis by means of indirect calorimetry, in 27 highly trained athletes and 27 sedentary, healthy men.ResultsTSH–FT3 ratio was lower in athletes (P<0.03), either in sustained power or anaerobic power-sprint athletes (n=13) or marathon runners (n=14). Whole body respiratory quotient was lower in athletes. Fasting serum sOB-R was higher and leptin lower in athletes than controls. Also serum adiponectin, resistin, and retinol binding protein-4 concentrations were different in athletes than in controls. The ratio between leptin and sOB-R, the free leptin index (FLI), was lower in athletes than in controls (0.025±0.014 vs 0.085±0.049; P<0.001). In multivariate analysis, FLI retained independent association with TSH–FT3 ratio.ConclusionMale, elite athletes had lower TSH–FT3 ratio and FLI than controls while FLI was independently associated with TSH–FT3 ratio supporting the hypothesis that the level of biologically active leptin is involved in the adaptive response of thyroid function in professional athletes.

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Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1909917116 ◽

2019 ◽

Vol 116 (47) ◽

pp. 23822-23828 ◽

Cited By ~ 8

Author(s):

Shintaro Yamaguchi ◽

Michael P. Franczyk ◽

Maria Chondronikola ◽

Nathan Qi ◽

Subhadra C. Gunawardana ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Cold Exposure ◽

Energy Homeostasis ◽

Lipolytic Activity ◽

Whole Body ◽

Brown Adipocyte ◽

Nicotinamide Phosphoribosyltransferase ◽

Adaptive Thermogenesis ◽

Body Energy

Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD+ metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD+ biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of β-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD+–SIRT1–caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD+ synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD+ biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

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Intestinal gluconeogenesis and protein diet: future directions

Proceedings of The Nutrition Society ◽

10.1017/s0029665120007922 ◽

2020 ◽

pp. 1-8

Author(s):

Amandine Gautier-Stein ◽

Fabienne Rajas ◽

Gilles Mithieux

Keyword(s):

Portal Vein ◽

Energy Homeostasis ◽

Glucose Sensing ◽

Endogenous Glucose Production ◽

Nutrient Sensing ◽

Whole Body ◽

Beneficial Effects ◽

Obesity And Diabetes ◽

Intestinal Gluconeogenesis ◽

Protein Diets

High-protein meals and foods are promoted for their beneficial effects on satiety, weight loss and glucose homeostasis. However, the mechanisms involved and the long-term benefits of such diets are still debated. We here review how the characterisation of intestinal gluconeogenesis (IGN) sheds new light on the mechanisms by which protein diets exert their beneficial effects on health. The small intestine is the third organ (in addition to the liver and kidney) contributing to endogenous glucose production via gluconeogenesis. The particularity of glucose produced by the intestine is that it is detected in the portal vein and initiates a nervous signal to the hypothalamic nuclei regulating energy homeostasis. In this context, we demonstrated that protein diets initiate their satiety effects indirectly via IGN and portal glucose sensing. This induction results in the activation of brain areas involved in the regulation of food intake. The μ-opioid-antagonistic properties of protein digests, exerted in the portal vein, are a key link between IGN induction and protein-enriched diet in the control of satiety. From our results, IGN can be proposed as a mandatory link between nutrient sensing and the regulation of whole-body homeostasis. The use of specific mouse models targeting IGN should allow us to identify several metabolic functions that could be controlled by protein diets. This will lead to the characterisation of the mechanisms by which protein diets improve whole-body homeostasis. These data could be the basis of novel nutritional strategies targeting the serious metabolic consequences of both obesity and diabetes.

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Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

Biomolecules ◽

10.3390/biom10111504 ◽

2020 ◽

Vol 10 (11) ◽

pp. 1504

Author(s):

Jie L. Tian ◽

Farzad Islami Gomeshtapeh

Keyword(s):

Energy Metabolism ◽

Energy Homeostasis ◽

Primary Cilia ◽

Active Role ◽

Eukaryotic Cells ◽

Β Cells ◽

Pancreatic Β Cells ◽

Metabolic Signaling ◽

Extracellular Signals ◽

Obesity And Diabetes

The primary cilium, an antenna-like structure on most eukaryotic cells, functions in transducing extracellular signals into intracellular responses via the receptors and ion channels distributed along it membrane. Dysfunction of this organelle causes an array of human diseases, known as ciliopathies, that often feature obesity and diabetes; this indicates the primary cilia’s active role in energy metabolism, which it controls mainly through hypothalamic neurons, preadipocytes, and pancreatic β-cells. The nutrient sensor, O-GlcNAc, is widely involved in the regulation of energy homeostasis. Not only does O-GlcNAc regulate ciliary length, but it also modifies many components of cilia-mediated metabolic signaling pathways. Therefore, it is likely that O-GlcNAcylation (OGN) plays an important role in regulating energy homeostasis in primary cilia. Abnormal OGN, as seen in cases of obesity and diabetes, may play an important role in primary cilia dysfunction mediated by these pathologies.

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The Impact of Single-Cell Genomics on Adipose Tissue Research

International Journal of Molecular Sciences ◽

10.3390/ijms21134773 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4773

Author(s):

Alana Deutsch ◽

Daorong Feng ◽

Jeffrey E. Pessin ◽

Kosaku Shinoda

Keyword(s):

Adipose Tissue ◽

Single Cell ◽

Energy Homeostasis ◽

Whole Body ◽

Diabetes Research ◽

Obesity And Diabetes ◽

Important Regulator ◽

Whole Body Metabolism ◽

Tissue Aging ◽

The Impact

Adipose tissue is an important regulator of whole-body metabolism and energy homeostasis. The unprecedented growth of obesity and metabolic disease worldwide has required paralleled advancements in research on this dynamic endocrine organ system. Single-cell RNA sequencing (scRNA-seq), a highly meticulous methodology used to dissect tissue heterogeneity through the transcriptional characterization of individual cells, is responsible for facilitating critical advancements in this area. The unique investigative capabilities achieved by the combination of nanotechnology, molecular biology, and informatics are expanding our understanding of adipose tissue’s composition and compartmentalized functional specialization, which underlie physiologic and pathogenic states, including adaptive thermogenesis, adipose tissue aging, and obesity. In this review, we will summarize the use of scRNA-seq and single-nuclei RNA-seq (snRNA-seq) in adipocyte biology and their applications to obesity and diabetes research in the hopes of increasing awareness of the capabilities of this technology and acting as a catalyst for its expanded use in further investigation.

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