p-Coumaric Acid Enhances Hypothalamic Leptin Signaling and Glucose Homeostasis in Mice via Differential Effects on AMPK Activation

AMP-activated protein kinase (AMPK) plays a crucial role in the regulation of energy homeostasis in both peripheral metabolic organs and the central nervous system. Recent studies indicated that p-Coumaric acid (CA), a hydroxycinnamic phenolic acid, potentially activated the peripheral AMPK pathway to exert beneficial effects on glucose metabolism in vitro. However, CA’s actions on central AMPK activity and whole-body glucose homeostasis have not yet been investigated. Here, we reported that CA exhibited different effects on peripheral and central AMPK activation both in vitro and in vivo. Specifically, while CA treatment promoted hepatic AMPK activation, it showed an inhibitory effect on hypothalamic AMPK activity possibly by activating the S6 kinase. Furthermore, CA treatment enhanced hypothalamic leptin sensitivity, resulting in increased proopiomelanocortin (POMC) expression, decreased agouti-related peptide (AgRP) expression, and reduced daily food intake. Overall, CA treatment improved blood glucose control, glucose tolerance, and insulin sensitivity. Together, these results suggested that CA treatment enhanced hypothalamic leptin signaling and whole-body glucose homeostasis, possibly via its differential effects on AMPK activation.

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Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

10.1101/749929 ◽

2019 ◽

Author(s):

Ana M. Cruz ◽

Yasaman Malekizadeh ◽

Julia M. Vlachaki Walker ◽

Paul G. Weightman Potter ◽

Katherine Pye ◽

...

Keyword(s):

Nervous System ◽

Autonomic Nervous System ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Ventromedial Hypothalamus ◽

Whole Body ◽

Ampk Activation ◽

Autonomic Nervous ◽

Glucose Levels

ABSTRACTAMP-activated protein kinase (AMPK) is a critical cellular and whole body energy sensor activated by energy stress, including hypoglycemia, which is frequently experienced by people with diabetes. Previous studies using direct delivery of an AMPK activator to the ventromedial hypothalamus (VMH) in rodents increased hepatic glucose production. Moreover, recurrent glucoprivation in the hypothalamus leads to blunted AMPK activation and defective hormonal responses to subsequent hypoglycemia. These data suggest that amplifying AMPK activation may prevent or reduce frequency hypoglycemia in diabetes. We used a novel brain-permeable AMPK activator, R481, which potently increased AMPK phosphorylation in vitro. R481 significantly increased peak glucose levels during glucose tolerance tests in rats, which were attenuated by treatment with AMPK inhibitor SBI-0206965 and completely abolished by blockade of the autonomic nervous system. This occurred without altering insulin sensitivity measured by hyperinsulinemic-euglycemic clamps. Endogenous insulin secretion was not altered by R481 treatment. During hyperinsulinemic-hypoglycemic clamp studies, R481 treatment reduced exogenous glucose requirements and amplified peak glucagon levels during hypoglycemia. These data demonstrate that peripheral administration of the brain permeable AMPK activator R481 amplifies the counterregulatory response to hypoglycemia in rats, which could have clinical relevance for prevention of hypoglycemia.

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A Hierarchical Whole-body Modeling Approach Elucidates the Link between in Vitro Insulin Signaling and in Vivo Glucose Homeostasis

Journal of Biological Chemistry ◽

10.1074/jbc.m110.188987 ◽

2011 ◽

Vol 286 (29) ◽

pp. 26028-26041 ◽

Cited By ~ 55

Author(s):

Elin Nyman ◽

Cecilia Brännmark ◽

Robert Palmér ◽

Jan Brugård ◽

Fredrik H. Nyström ◽

...

Keyword(s):

Glucose Homeostasis ◽

Insulin Signaling ◽

Whole Body ◽

Modeling Approach

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Selective Inactivation of Socs3 in SF1 Neurons Improves Glucose Homeostasis without Affecting Body Weight

Endocrinology ◽

10.1210/en.2008-0805 ◽

2008 ◽

Vol 149 (11) ◽

pp. 5654-5661 ◽

Cited By ~ 59

Author(s):

Ren Zhang ◽

Harveen Dhillon ◽

Huali Yin ◽

Akihiko Yoshimura ◽

Bradford B. Lowell ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Glucose Homeostasis ◽

Leptin Resistance ◽

High Fat ◽

Leptin Signaling ◽

Leptin Sensitivity ◽

High Fat Diets ◽

Fat Diets

Suppressor of cytokine signaling 3 (Socs3) has been identified as a mediator of central leptin resistance, but the identity of specific neurons in which Socs3 acts to suppress leptin signaling remains elusive. The ventromedial hypothalamus (VMH) was recently shown to be an important site for leptin action because deleting leptin receptor within VMH neurons causes obesity. To examine the role of VMH Socs3 in leptin resistance and energy homeostasis, we generated mice lacking Socs3 specifically in neurons positive for steroidogenic factor 1 (SF1), which is expressed abundantly in the VMH. These mice had increased phosphorylation of signal transducer and activator of transcription-3 in VMH neurons, suggesting improved leptin signaling, and consistently, food intake and weight-reducing effects of exogenous leptin were enhanced. Furthermore, on either chow or high-fat diets, these mice had reduced food intake. Unexpectedly, energy expenditure was reduced as well. Mice lacking Socs3 in SF1 neurons, despite no change in body weight, had improved glucose homeostasis and were partially protected from hyperglycemia and hyperinsulinemia induced by high-fat diets. These results suggest that Socs3 in SF1 neurons negatively regulates leptin signaling and plays important roles in mediating leptin sensitivity, glucose homeostasis, and energy expenditure.

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Role of Exchange Protein Directly Activated by Cyclic AMP Isoform 1 in Energy Homeostasis: Regulation of Leptin Expression and Secretion in White Adipose Tissue

Molecular and Cellular Biology ◽

10.1128/mcb.01034-15 ◽

2016 ◽

Vol 36 (19) ◽

pp. 2440-2450 ◽

Cited By ~ 13

Author(s):

Yaohua Hu ◽

William G. Robichaux ◽

Fang C. Mei ◽

Eun Ran Kim ◽

Hui Wang ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Balance ◽

Cyclic Amp ◽

Glucose Homeostasis ◽

White Adipose Tissue ◽

Energy Homeostasis ◽

Leptin Sensitivity ◽

Leptin Expression

Epacs (exchange proteins directly activated by cyclic AMP [cAMP]) act as downstream effectors of cAMP and play important roles in energy balance and glucose homeostasis. While global deletion of Epac1 in mice leads to heightened leptin sensitivity in the hypothalamus and partial protection against high-fat diet (HFD)-induced obesity, the physiological functions of Epac1 in white adipose tissue (WAT) has not been explored. Here, we report that adipose tissue-specific Epac1 knockout (AEKO) mice are more prone to HFD-induced obesity, with increased food intake, reduced energy expenditure, and impaired glucose tolerance. Despite the fact that AEKO mice on HFD display increased body weight, these mice have decreased circulating leptin levels compared to their wild-type littermates.In vivoandin vitroanalyses further reveal that suppression of Epac1 in WAT decreases leptin mRNA expression and secretion by inhibiting cAMP response element binding (CREB) protein and AKT phosphorylation, respectively. Taken together, our results demonstrate that Epac1 plays an important role in regulating energy balance and glucose homeostasis by promoting leptin expression and secretion in WAT.

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Neuronal Protein Tyrosine Phosphatase 1B Deficiency Results in Inhibition of Hypothalamic AMPK and Isoform-Specific Activation of AMPK in Peripheral Tissues

Molecular and Cellular Biology ◽

10.1128/mcb.01914-08 ◽

2009 ◽

Vol 29 (16) ◽

pp. 4563-4573 ◽

Cited By ~ 59

Author(s):

Bingzhong Xue ◽

Thomas Pulinilkunnil ◽

Incoronata Murano ◽

Kendra K. Bence ◽

Huamei He ◽

...

Keyword(s):

Energy Expenditure ◽

Target Genes ◽

Fiber Type ◽

Metabolic Effects ◽

Whole Body ◽

Acid Oxidation ◽

Peripheral Tissues ◽

Leptin Sensitivity ◽

Brown Adipose ◽

Ampk Activity

ABSTRACT PTP1B−/− mice are resistant to diet-induced obesity due to leptin hypersensitivity and consequent increased energy expenditure. We aimed to determine the cellular mechanisms underlying this metabolic state. AMPK is an important mediator of leptin's metabolic effects. We find that α1 and α2 AMPK activity are elevated and acetyl-coenzyme A carboxylase activity is decreased in the muscle and brown adipose tissue (BAT) of PTP1B−/− mice. The effects of PTP1B deficiency on α2, but not α1, AMPK activity in BAT and muscle are neuronally mediated, as they are present in neuron- but not muscle-specific PTP1B−/− mice. In addition, AMPK activity is decreased in the hypothalamic nuclei of neuronal and whole-body PTP1B−/− mice, accompanied by alterations in neuropeptide expression that are indicative of enhanced leptin sensitivity. Furthermore, AMPK target genes regulating mitochondrial biogenesis, fatty acid oxidation, and energy expenditure are induced with PTP1B inhibition, resulting in increased mitochondrial content in BAT and conversion to a more oxidative muscle fiber type. Thus, neuronal PTP1B inhibition results in decreased hypothalamic AMPK activity, isoform-specific AMPK activation in peripheral tissues, and downstream gene expression changes that promote leanness and increased energy expenditure. Therefore, the mechanism by which PTP1B regulates adiposity and leptin sensitivity likely involves the coordinated regulation of AMPK in hypothalamus and peripheral tissues.

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Reducing hepatic PKD activity lowers circulating VLDL cholesterol

Journal of Endocrinology ◽

10.1530/joe-19-0548 ◽

2020 ◽

Vol 246 (3) ◽

pp. 265-276 ◽

Cited By ~ 1

Author(s):

Amanda J Genders ◽

Timothy Connor ◽

Shona Morrison ◽

Simon T Bond ◽

Brian G Drew ◽

...

Keyword(s):

Glucose Homeostasis ◽

Dominant Negative ◽

Whole Body ◽

Protein Kinase D ◽

Adeno Associated Virus ◽

Vldl Cholesterol ◽

Insulin Tolerance ◽

Fatty Acid Accumulation ◽

Fasting And Refeeding

Protein kinase D (PKD) is emerging as an important kinase regulating energy balance and glucose metabolism; however, whether hepatic PKD activity can be targeted to regulate these processes is currently unclear. In this study, hepatic PKD activity was reduced using adeno-associated virus vectors to express a dominant-negative (DN) version of PKD1, which impairs the action of all three PKD isoforms. In chow-fed mice, hepatic DN PKD expression increased whole-body glucose oxidation, but had only mild effects on glucose and insulin tolerance and no effects on glucose homeostasis following fasting and refeeding. However, circulating VLDL cholesterol was reduced under these conditions and was associated with hepatic fatty acid accumulation, but not lipids involved in lipoprotein synthesis. The limited effects on glucose homeostasis in DN PKD mice was despite reduced expression of gluconeogenic genes under both fasted and refed conditions, and enhanced pyruvate tolerance. The requirement for PKD for gluconeogenic capacity was supported by in vitro studies in cultured FAO hepatoma cells expressing DN PKD, which produced less glucose under basal conditions. Although these pathways are increased in obesity, the expression of DN PKD in the liver of mice fed a high-fat diet had no impact on glucose tolerance, insulin action, pyruvate tolerance or plasma VLDL. Together, these data suggest that PKD signalling in the liver regulates metabolic pathways involved in substrate redistribution under conditions of normal nutrient availability, but not under conditions of overnutrition such as in obesity.

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Galectin-3 gene deletion results in defective adipose tissue maturation and impaired insulin sensitivity and glucose homeostasis

Scientific Reports ◽

10.1038/s41598-020-76952-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Claudia Blasetti Fantauzzi ◽

Carla Iacobini ◽

Stefano Menini ◽

Martina Vitale ◽

Gian Pio Sorice ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Cell Function ◽

Whole Body ◽

Metabolic Derangement ◽

Abnormal Glucose Regulation ◽

Galectin 3 ◽

Β Cell Function

AbstractAdiposopathy is a pathological adipose tissue (AT) response to overfeeding characterized by reduced AT expandability due to impaired adipogenesis, which favors inflammation, insulin resistance (IR), and abnormal glucose regulation. However, it is unclear whether defective adipogenesis causes metabolic derangement also independently of an increased demand for fat storage. As galectin-3 has been implicated in both adipocyte differentiation and glucose homeostasis, we tested this hypothesis in galectin-3 knockout (Lgal3−/−) mice fed a standard chow. In vitro, Lgal3−/− adipocyte precursors showed impaired terminal differentiation (maturation). Two-month-old Lgal3−/− mice showed impaired AT maturation, with reduced adipocyte size and expression of adipogenic genes, but unchanged fat mass and no sign of adipocyte degeneration/death or ectopic fat accumulation. AT immaturity was associated with AT and whole-body inflammation and IR, glucose intolerance, and hyperglycemia. Five-month-old Lgal3−/− mice exhibited a more mature AT phenotype, with no difference in insulin sensitivity and expression of inflammatory cytokines versus WT animals, though abnormal glucose homeostasis persisted and was associated with reduced β-cell function. These data show that adipogenesis capacity per se affects AT function, insulin sensitivity, and glucose homeostasis independently of increased fat intake, accumulation and redistribution, thus uncovering a direct link between defective adipogenesis, IR and susceptibility to diabetes.

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Mathematical Modeling for the Physiological and Clinical Investigation of Glucose Homeostasis and Diabetes

Frontiers in Physiology ◽

10.3389/fphys.2020.575789 ◽

2020 ◽

Vol 11 ◽

Author(s):

Andrea Mari ◽

Andrea Tura ◽

Eleonora Grespan ◽

Roberto Bizzotto

Keyword(s):

Mathematical Modeling ◽

Glucose Homeostasis ◽

Cell Function ◽

Clinical Investigation ◽

Experimental Tests ◽

Whole Body ◽

Mathematical Representation ◽

Use Of Models

Mathematical modeling in the field of glucose metabolism has a longstanding tradition. The use of models is motivated by several reasons. Models have been used for calculating parameters of physiological interest from experimental data indirectly, to provide an unambiguous quantitative representation of pathophysiological mechanisms, to determine indices of clinical usefulness from simple experimental tests. With the growing societal impact of type 2 diabetes, which involves the disturbance of the glucose homeostasis system, development and use of models in this area have increased. Following the approaches of physiological and clinical investigation, the focus of the models has spanned from representations of whole body processes to those of cells, i.e., from in vivo to in vitro research. Model-based approaches for linking in vivo to in vitro research have been proposed, as well as multiscale models merging the two areas. The success and impact of models has been variable. Two kinds of models have received remarkable interest: those widely used in clinical applications, e.g., for the assessment of insulin sensitivity and β-cell function and some models representing specific aspects of the glucose homeostasis system, which have become iconic for their efficacy in describing clearly and compactly key physiological processes, such as insulin secretion from the pancreatic β cells. Models are inevitably simplified and approximate representations of a physiological system. Key to their success is an appropriate balance between adherence to reality, comprehensibility, interpretative value and practical usefulness. This has been achieved with a variety of approaches. Although many models concerning the glucose homeostasis system have been proposed, research in this area still needs to address numerous issues and tackle new opportunities. The mathematical representation of the glucose homeostasis processes is only partial, also because some mechanisms are still only partially understood. For in vitro research, mathematical models still need to develop their potential. This review illustrates the problems, approaches and contribution of mathematical modeling to the physiological and clinical investigation of glucose homeostasis and diabetes, focusing on the most relevant and stimulating models.

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Minimal contribution of cell-bound antibodies to the immunoscintigraphy of inflamed joints with 99mTc-anti-CD4 monoclonal antibodies

Nuklearmedizin ◽

10.1055/s-0038-1623888 ◽

2002 ◽

Vol 41 (03) ◽

pp. 129-134 ◽

Cited By ~ 4

Author(s):

A. Wolski ◽

E. Palombo-Kinne ◽

F. Wolf ◽

F. Emmrich ◽

W. Becker ◽

...

Keyword(s):

T Cells ◽

Monoclonal Antibodies ◽

Synovial Membrane ◽

In Vitro Release ◽

Peritoneal Macrophages ◽

Lymphoid Organs ◽

Whole Body ◽

Free Form ◽

Ankle Joints

Summary Aim: The cellular joint infiltrate in rheumatoid arthritis patients is rich in CD4-positive T-helper lymphocytes and macrophages, rendering anti-CD4 monoclonal antibodies (mAbs) suitable for specific immunoscintigraphy of human/ experimental arthritis. Following intravenous injection, however, mAbs are present both in the free form and bound to CD4-positive, circulating monocytes and T-cells. Thus, the present study aimed at analyzing the relative contribution of the free and the cell-bound component to the imaging of inflamed joints in experimental adjuvant arthritis (AA). Methods: AA rat peritoneal macrophages or lymph node T-cells were incubated in vitro with saturating amounts of 99mTc-anti-CD4 mAb (W3/25) and injected i.v. into rats with AA. Results: In vitro release of 99mTc-anti-CD4 mAb from the cells was limited (on average 1.57%/h for macrophages and 0.84%/h for T-cells). Following i.v. injection, whole body/joint scans and tissue measurements showed only negligible accumulation of radioactivity in inflamed ankle joints (tissue: 0.22 and 0.34% of the injected activity, respectively), whereas the radioactivity was concentrated in liver (tissue: 79% and 71%, respectively), kidney, and urinary bladder. Unlike macrophages, however, anti-CD4 mAb-coated T-cells significantly accumulated in lymphoid organs, the inflamed synovial membrane of the ankle joints, as well as in elbow and knee joints. Conclusion: While the overall contribution of cell-bound mAbs to the imaging of arthritic joints with anti-CD4 mAbs is minimal, differential accumulation of macrophages and T-cells in lymphoid organs and the inflamed synovial membrane indicates preferential migration patterns of these 2 cell populations in arthritic rats. Although only validated for 99mTc-anti-CD4 mAbs, extrapolation of the results to other anticellular mAbs with similar affinity for their antigen may be possible.

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A Simple and Inexpensive Clinical Whole Body Counter

Nuklearmedizin ◽

10.1055/s-0038-1624972 ◽

1976 ◽

Vol 15 (05) ◽

pp. 248-253

Author(s):

A. K. Basu ◽

S. K. Guha ◽

B. N. Tandon ◽

M. M. Gupta ◽

M. ML. Rehani

Keyword(s):

The Body ◽

Whole Body ◽

Vitro Assay ◽

Body Counter ◽

Optimum Parameters ◽

Whole Body Counter ◽

Single Detector ◽

Background Index ◽

Iodide Crystal

SummaryThe conventional radioisotope scanner has been used as a whole body counter. The background index of the system is 10.9 counts per minute per ml of sodium iodide crystal. The sensitivity and derived sensitivity parameters have been evaluated and found to be suitable for clinical studies. The optimum parameters for a single detector at two positions above the lying subject have been obtained. It has been found that for the case of 131I measurement it is possible to assay a source located at any point in the body with coefficient of variation less than 5%. To add to the versatility, a fixed geometry for in-vitro counting of large samples has been obtained. The retention values obtained by the whole body counter have been found to correlate with those obtained by in-vitro assay of urine and stool after intravenous administration of 51Cr-albumin.

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