scholarly journals CB1 receptor mediates the effects of glucocorticoids on AMPK activity in the hypothalamus

2013 ◽  
Vol 219 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Miski Scerif ◽  
Tamás Füzesi ◽  
Julia D Thomas ◽  
Blerina Kola ◽  
Ashley B Grossman ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Energy Homeostasis ◽  
Cardiac Tissue ◽  
Cannabinoid Receptor ◽  
Cushing's Syndrome ◽  
Cb1 Receptor ◽  
Metabolic Effects ◽  
Glucocorticoid Treatment ◽  
Adipose Tissues ◽  
Ampk Activity

AMP-activated protein kinase (AMPK), a regulator of cellular and systemic energy homeostasis, can be influenced by several hormones. Tissue-specific alteration of AMPK activity by glucocorticoids may explain the increase in appetite, the accumulation of lipids in adipose tissues, and the detrimental cardiac effects of Cushing's syndrome. Endocannabinoids are known to mediate the effects of various hormones and to influence AMPK activity. Cannabinoids have central orexigenic and direct peripheral metabolic effects via the cannabinoid receptor type 1 (CB1). In our preliminary experiments, WT mice received implants of a corticosterone-containing pellet to establish a mouse model of Cushing's syndrome. Subsequently, WT andCb1(Cnr1)-knockout (CB1-KO) littermates were treated with corticosterone and AMPK activity in the hypothalamus, various adipose tissues, liver and cardiac tissue was measured. Corticosterone-treated CB1-KO mice showed a lack of weight gain and of increase in hypothalamic and hepatic AMPK activity. In adipose tissues, baseline AMPK activity was higher in CB1-KO mice, but a glucocorticoid-induced drop was observed, similar to that observed in WT mice. Cardiac AMPK levels were reduced in CB1-KO mice, but while WT mice showed significantly reduced AMPK activity following glucocorticoid treatment, CB1-KO mice showed a paradoxical increase. Our findings indicate the importance of the CB1 receptor in the central orexigenic effect of glucocorticoid-induced activation of hypothalamic AMPK activity. In the periphery adipose tissues, changes may occur independently of the CB1 receptor, but the receptor appears to alter the responsiveness of the liver and myocardial tissues to glucocorticoids. In conclusion, our data suggest that an intact cannabinoid pathway is required for the full metabolic effects of chronic glucocorticoid excess.

scholarly journals Changes in Adenosine 5′-Monophosphate-Activated Protein Kinase as a Mechanism of Visceral Obesity in Cushing’s Syndrome

2008 ◽  
Vol 93 (12) ◽  
pp. 4969-4973 ◽  
Author(s):  
Blerina Kola ◽  
Mirjam Christ-Crain ◽  
Francesca Lolli ◽  
Giorgio Arnaldi ◽  
Gilberta Giacchetti ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Protein Kinase ◽  
Abdominal Surgery ◽  
Visceral Adipose Tissue ◽  
Cushing’S Syndrome ◽  
Central Obesity ◽  
Cushing's Syndrome ◽  
Metabolic Effects ◽  
Ampk Activity ◽  
Visceral Adipose

Objective: Features of the metabolic syndrome such as central obesity with insulin resistance and dyslipidemia are typical signs of Cushing’s syndrome and common side effects of prolonged glucocorticoid treatment. AMP-activated protein kinase (AMPK), a key regulatory enzyme of lipid and carbohydrate metabolism as well as appetite, is involved in the development of the deleterious metabolic effects of excess glucocorticoids, but no data are available in humans. In the current study, we demonstrate the effect of high glucocorticoid levels on AMPK activity of human adipose tissue samples from patients with Cushing’s syndrome. Methods: AMPK activity and mRNA expression of genes involved in lipid metabolism were assessed in visceral adipose tissue removed at abdominal surgery of 11 patients with Cushing’s syndrome, nine sex-, age-, and weight-matched patients with adrenal incidentalomas, and in visceral adipose tissue from four patients with non-endocrine-related abdominal surgery. Results: The patients with Cushing’s syndrome exhibited a 70% lower AMPK activity in visceral adipose tissue as compared with both incidentalomas and control patients (P = 0.007 and P < 0.001, respectively). Downstream targets of AMPK fatty acid synthase and phosphoenol-pyruvate carboxykinase were up-regulated in patients with Cushing’s syndrome. AMPK activity was inversely correlated with 0900 h serum cortisol and with urinary free cortisol. Conclusions: Our data suggest that glucocorticoids inhibit AMPK activity in adipose tissue, suggesting a novel mechanism to explain the deposition of visceral adipose tissue and the consequent central obesity observed in patients with iatrogenic or endogenous Cushing’s syndrome.

scholarly journals Endocannabinoids and Their Receptors as Targets for Obesity Therapy

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2531-2536 ◽  
Author(s):  
Annette D. de Kloet ◽  
Stephen C. Woods
Keyword(s):  
Energy Homeostasis ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
Metabolic Effects ◽  
Peripheral Tissues ◽  
Anabolic Action ◽  
Obesity Therapy ◽  
Glucose Profiles ◽  
Cb1 Antagonists

As the incidence of obesity continues to increase, the development of effective therapies is a high priority. The endocannabinoid system has emerged as an important influence on the regulation of energy homeostasis. The endocannabinoids anandamide and 2-arachidonoylglycerol act on cannabinoid receptor-1 (CB1) in the brain and many peripheral tissues causing a net anabolic action. This includes increasing food intake, and causing increased lipogenesis and fat storage in adipose tissue and liver. The endocannabinoid system is hyperactive in obese humans and animals, and treating them with CB1 antagonists causes weight loss and improved lipid and glucose profiles. Although clinical trials with CB1 antagonists have yielded beneficial metabolic effects, concerns about negative affect have limited the therapeutic potential of the first class of CB1 antagonists available.

scholarly journals Iatrogenic Cushing’s Syndrome Due to Topical Ocular Glucocorticoid Treatment

PEDIATRICS ◽  
2017 ◽  
Vol 139 (2) ◽  
pp. e20161233 ◽  
Author(s):  
Daisuke Fukuhara ◽  
Toshihiko Takiura ◽  
Hiroshi Keino ◽  
Annabelle A. Okada ◽  
Kunimasa Yan
Keyword(s):  
Cushing’S Syndrome ◽  
Cushing's Syndrome ◽  
Glucocorticoid Treatment ◽  
Iatrogenic Cushing’S Syndrome

scholarly journals Thioredoxin Interacting Protein Is a Potential Regulator of Glucose and Energy Homeostasis in Endogenous Cushing's Syndrome

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e64247 ◽  
Author(s):  
Tove Lekva ◽  
Jens Bollerslev ◽  
Afaf Sahraoui ◽  
Hanne Scholz ◽  
Hege Bøyum ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Energy Homeostasis ◽  
Cushing's Syndrome ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein

Natriuretic peptides and cGMP signaling control of energy homeostasis

2013 ◽  
Vol 304 (3) ◽  
pp. H358-H368 ◽  
Author(s):  
Cedric Moro ◽  
Max Lafontan
Keyword(s):  
Skeletal Muscle ◽  
Natriuretic Peptides ◽  
Energy Homeostasis ◽  
Biological Effects ◽  
Metabolic Effects ◽  
Adipose Tissues ◽  
Metabolic Role ◽  
Brown Adipose ◽  
Cgmp Signaling

Since the discovery of natriuretic peptides (NPs) by de Bold et al. in 1981, the cardiovascular community has been well aware that they exert potent effects on vessels, heart remodeling, kidney function, and the regulation of sodium and water balance. Who would have thought that NPs are also able to exert metabolic effects and contribute to an original cross talk between heart, adipose tissues, and skeletal muscle? The attention on the metabolic role of NPs was awakened in the year 2000 with the discovery that NPs exert potent lipolytic effects mediated by the NP receptor type A/cGMP pathway in human fat cells and that they contribute to lipid mobilization in vivo. In this review, we will discuss the biological effects of NPs on the main tissues involved in the regulation of energy metabolism (i.e., white and brown adipose tissues, skeletal muscle, liver, and pancreas). These recent results on NPs are opening a new chapter into the physiological properties and therapeutic usefulness of this family of hormones.

scholarly journals Mechanisms in Endocrinology: LOCAL AND SYSTEMIC EFFECTS OF GLUCOCORTICOIDS ON METABOLISM: NEW LESSONS FROM ANIMAL MODELS

2021 ◽  
Author(s):  
Michael Swarbrick ◽  
Hong Zhou ◽  
Markus Seibel
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Visceral Obesity ◽  
Metabolic Effects ◽  
Glucocorticoid Treatment ◽  
Brown Adipose ◽  
Nutrient Partitioning ◽  
Brown Adipose Tissue Thermogenesis

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores, but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is therefore critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (11β-HSD1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive 11β-HSD1 activity, amplifying local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and aging-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated the mechanisms by which glucocorticoids exert their metabolic effects; and have guided us towards more targeted future treatments for metabolic diseases.

scholarly journals Responses to the cannabinoid receptor-1 antagonist, AM251, are more robust with age and with high-fat feeding

2009 ◽  
Vol 203 (2) ◽  
pp. 281-290 ◽  
Author(s):  
M K Judge ◽  
Y Zhang ◽  
P J Scarpace
Keyword(s):  
Receptor Antagonist ◽  
Energy Homeostasis ◽  
Cannabinoid Receptor ◽  
Underlying Mechanism ◽  
Cb1 Receptor ◽  
Calorie Intake ◽  
Aged Rats ◽  
High Fat ◽  
Age Related ◽  
Cb1 Receptor Antagonist

Endocannabinoids (EC) are involved in regulating energy homeostasis, particularly in promoting hyperphagia and the consumption of a palatable diet. We have previously shown that rats given a high-fat (HF) diet display a transient hyperphagia that is normalized by a process partially dependent on leptin. We now propose that the induction of this hyperphagia is mediated, at least partially, by the EC signaling system. Obesity, including diet-induced and age-related, is associated with dysregulation of the EC system, and obese rodent models are hypersensitive to a cannabinoid-1 (CB1) receptor antagonist. This suggests that aged rats will be more responsive to the anorectic effects of a CB1 receptor antagonist. To test this, we examined the responsiveness to CB1 receptor antagonist, AM251, in young and aged rats during two experimental paradigms. First, we administered AM251 simultaneously with the introduction of an HF diet. Second, AM251 treatment began after the establishment of diet-induced obesity. Responses were measured by changes in body weight and composition, calorie intake, serum leptin, and biochemical indicators. The results demonstrated three key findings. 1) CB1 receptor activity contributes to the hyperphagia seen with the introduction of an HF diet. 2) Increased AM251 sensitivity and efficacy is increased with age and HF feeding, with the greatest responsiveness observed in HF-fed, aged rats. 3) AM251 sensitivity is elevated to a greater extent with HF diet than with established obesity. Thus, both age and an HF diet are associated with enhanced anorectic responses to AM251, but the underlying mechanism of these responses remains speculative.

scholarly journals Adrenal Insufficiency Secondary to Septic Shock in a Male Patient with Iatrogenic Cushing’s Syndrome: 2 sides of the Same Coin?

2021 ◽  
Vol 14 ◽  
pp. 117955142110266
Author(s):  
Luca Foppiani
Keyword(s):  
Septic Shock ◽  
Adrenal Insufficiency ◽  
Cushing’S Syndrome ◽  
Cushing's Syndrome ◽  
Stressful Events ◽  
Glucocorticoid Therapy ◽  
Relative Adrenal Insufficiency ◽  
Glucocorticoid Treatment ◽  
Life Saving ◽  
Severe Infections

Cushing’s syndrome causes increased morbidity and mortality due to cardiovascular and infectious diseases. Exogenous Cushing’s syndrome can render the adrenal glands unable to cope with severe infections and may result in Addisonian crisis, which can be fatal if not properly diagnosed and treated. During hospitalization for disease exacerbation, a man on chronic glucocorticoid therapy for Crohn’s disease and Cushingoid features developed polymicrobial septic shock together with hypotension that was unresponsive to fluids. On suspicion of relative adrenal insufficiency (cortisol levels were “inadequately” normal), intravenous hydrocortisone was started; norepinephrine was also required to normalize blood pressure. Following clinical improvement, oral cortisone acetate was started. On discharge, he was instructed on how to manage stressful events by increasing oral glucocorticoid treatment or starting a parenteral formulation, if required. Chronic glucocorticoid therapy can cause severe side-effects; in addition, hypoadrenalism can occur in critical illnesses (eg, severe infections). Prompt recognition and proper therapy of this condition can be life-saving.

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