Sympathetic Innervation of White Adipose Tissue: to Beige or Not to Beige?

Physiology ◽  
2021 ◽  
Vol 36 (4) ◽  
pp. 246-255
Author(s):  
Heike Münzberg ◽  
Elizabeth Floyd ◽  
Ji Suk Chang
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Metabolic Regulation ◽  
Current Knowledge ◽  
Sympathetic Innervation ◽  
Neuronal Circuits ◽  
Brown Adipocytes ◽  
White Adipocyte ◽  
Obesity Research ◽  
Neuronal Regulation

Obesity research progresses in understanding neuronal circuits and adipocyte biology to regulate metabolism. However, the interface of neuro-adipocyte interaction is less studied. We summarize the current knowledge of adipose tissue innervation and interaction with adipocytes and emphasize adipocyte transitions from white to brown adipocytes and vice versa. We further highlight emerging concepts for the differential neuronal regulation of brown/beige versus white adipocyte and the interdependence of both for metabolic regulation.

scholarly journals Neuronal Modulation of Brown Adipose Activity Through Perturbation of White Adipocyte Lipogenesis

2018 ◽  
Author(s):  
Adilson Guilherme ◽  
David J Pedersen ◽  
Felipe Henriques ◽  
Alexander H. Bedard ◽  
Elizabeth Henchey ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Fatty Acid Synthase ◽  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Long Distance ◽  
Brown Adipocytes ◽  
White Adipocyte ◽  
Brown Adipose ◽  
Beige Adipocytes

ABSTRACTWhite adipose tissue (WAT) secretes factors to communicate with other metabolic organs to maintain energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) causes expansion of sympathetic neurons within white adipose tissue (WAT) and the appearance of “beige” adipocytes. Here we report evidence that white adipocyte DNL activity is also coupled to neuronal regulation and thermogenesis in brown adipose tissue (BAT). Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. In contrast, selective ablation of FASN in brown adipocytes of mice (iUCP1FASNKO) failed to modulate sympathetic innervation and the thermogenic program in BAT. Surprisingly, DNL in brown adipocytes was also dispensable in maintaining euthermia when UCP1FASNKO mice were cold-exposed. These results indicate that DNL in white adipocytes influences long distance signaling to BAT, which can modify BAT sympathetic innervation and expression of genes involved in thermogenesis.

scholarly journals Noradrenaline and ATP regulate white adipocyte adiponectin exocytosis: disturbed adrenergic and purinergic signalling in obesity-associated diabetes

2021 ◽  
Author(s):  
Saliha Musovic ◽  
Ali M. Komai ◽  
Marina Kalds Said ◽  
Yanling Wu ◽  
Ingrid Wernstedt Asterholm ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Adrenergic Receptors ◽  
Sympathetic Innervation ◽  
Sympathetic Nerves ◽  
Purinergic Signalling ◽  
Diabetic Mice ◽  
White Adipocyte ◽  
Hmw Adiponectin ◽  
Circulating Levels

AbstractWhite adipocyte adiponectin exocytosis is triggered by cAMP and a concomitant increase of cytosolic Ca2+ potentiates its release. White adipose tissue is richly innervated by sympathetic nerves co-releasing noradrenaline (NA) and ATP that may act on receptors in the adipocyte plasma membrane to increase cAMP via adrenergic receptors and Ca2+ via purinergic receptors, respectively. Here we determine the importance of NA and ATP for the regulation of white adipocyte adiponectin exocytosis, at the cellular and molecular level, and we specifically detail the ATP signalling pathway. Immunohistochemical staining demonstrates that tyrosine hydroxylase (enzyme involved in catecholamine synthesis) is dramatically reduced in inguinal white adipose tissue (IWAT) isolated from mice with diet-induced obesity; this is associated with diminished levels of NA in IWAT and with lowered serum adiponectin. Adiponectin exocytosis (measured as increase in plasma membrane capacitance and as secreted product) is triggered by NA or ATP alone in cultured and primary mouse IWAT adipocytes, and enhanced by a combination of the two secretagogues. The ATP-induced adiponectin exocytosis is largely Ca2+-dependent and activated via P2Y2 receptors (P2Y2Rs) and the Gq11/PLC pathway. Adiponectin release induced by the nucleotide is abrogated in adipocytes isolated from obese/diabetic mice and this is associated with ∼70% reduced abundance of P2Y2Rs. The NA-triggered adiponectin exocytosis is likewise abolished in “obese adipocytes”, concomitant with a 50% lower gene expression of beta 3 adrenergic receptors (β3ARs). The NA-stimulated adiponectin secretion does not contain Ca2+-dependent components. Collectively, our data suggest that sympathetic innervation is a principal regulator of adiponectin exocytosis and that disruptions of this control are associated with the obesity-associated reduction of circulating levels of HMW adiponectin.Key point listWhite adipose tissue is richly innervated by sympathetic nerves that co-release noradrenaline (NA) and ATP.Protein levels of tyrosine hydroxylase and NA are dramatically decreased in white adipose tissue from obese/diabetic mice, concomitant with reduced serum levels of high-molecular weight (HMW) adiponectin.NA and ATP stimulate white adipocyte adiponectin exocytosis via beta adrenergic and purinergic receptors respectively. The ATP-induced adiponectin secretion is chiefly Ca2+-dependent and activated via the P2Y2/Gq11/PLC pathway.The purinergic signalling is abrogated in adipocytes from obese/diabetic mice, due to reduced abundance of P2Y2Rs. The response to NA is likewise abolished in “obese adipocytes”, associated with lowered gene expression of beta 3 adrenergic receptors (β3ARs).We propose that sympathetic innervation is central in regulation of adiponectin exocytosis via co-secretion of NA and ATP and that this control is disrupted in obesity-associated diabetes, leading to lower circulating levels of HMW adiponectin.

scholarly journals Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anastasia Georgiadi ◽  
Valeria Lopez-Salazar ◽  
Rabih El- Merahbi ◽  
Rhoda Anane Karikari ◽  
Xiaochuan Ma ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Dependent Manner ◽  
Metabolic Dysfunction ◽  
Functional Interaction ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Obesity And Diabetes ◽  
Adhesion Gpcr ◽  
Circulating Levels

AbstractThe proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

scholarly journals Ubc9 deletion in adipocytes causes lipoatrophy in mice

2020 ◽  
Author(s):  
Aaron R. Cox ◽  
Natasha Chernis ◽  
Kang Ho Kim ◽  
Peter M. Masschelin ◽  
Pradip K. Saha ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Balance ◽  
Hepatic Steatosis ◽  
Postnatal Growth ◽  
Endocrine Control ◽  
Brown Adipocytes ◽  
Human Adipocyte ◽  
White Adipocyte ◽  
Adipose Tissue Depots

ABSTRACTObjectiveWhite adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. WAT absence or loss occurring through lipodystrophy and lipoatrophy contributes to the development of dyslipidemia, hepatic steatosis, and insulin resistance. We previously demonstrated the sole small ubiquitin-like modifier (SUMO) E2-conjuguating enzyme Ubc9 represses human adipocyte differentiation. Germline and other tissue-specific deletions of Ubc9 frequently cause lethality in mice. As a result, the role of Ubc9 during WAT development remains unknown.MethodsTo determine how Ubc9 impacts body composition and energy balance, we generated adipocyte-specific Ubc9 knockout mice (Ubc9a-KO). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ubc9 locus. Subsequent genetic crosses to AdipoQ-Cre transgenic mice allowed deletion of Ubc9 in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ubc9a-KO and littermate controls during postnatal growth.ResultsTo our surprise, Ubc9a-KO mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period.ConclusionsOur results demonstrate that Ubc9 expression in mature adipocytes is essential for maintaining WAT expansion. Deletion of Ubc9 in fat cells compromised and diminished adipocyte function that provoked WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ubc9 during white adipocyte expansion and endocrine control of energy balance.

scholarly journals Lung Cancer Cachexia: Can Molecular Understanding Guide Clinical Management?

2018 ◽  
Vol 17 (3) ◽  
pp. 1000-1008 ◽  
Author(s):  
Jonas Sørensen
Keyword(s):  
Lung Cancer ◽  
Adipose Tissue ◽  
Food Intake ◽  
White Adipose Tissue ◽  
Clinical Management ◽  
Cancer Cachexia ◽  
Screening Tool ◽  
Current Knowledge ◽  
Host Immune System ◽  
Abnormal Metabolism

Cachexia has been recognized for a long time as an adverse effect of cancer. It is associated with reduced physical function, reduced tolerance to anticancer therapy, and reduced survival. This wasting syndrome is mainly known for an ongoing loss of skeletal muscle leading to progressive functional impairment and is driven by a variable combination of reduced food intake and abnormal metabolism. Cytokines derived from host immune system or the tumor itself is believed to play a role in promoting cancer cachexia. Circulating levels of cytokines, including IL-1α, IL-6, and TNFα have been identified in cancer patients but they probably only represent a small part of a changed and abnormal metabolism. Murine models have shown that browning of white adipose tissue (WAT) takes place early in the progression of cancer cachexia. Thus, browning of white adipose tissue is believed to be a strong contributor to the increased energy expenditure common in cachectic patients. Despite the severe implications of cancer cachexia for the patients and extensive research efforts, a more coherent and mechanistic explanation of the syndrome is lacking, and for many clinicians, cancer cachexia is still a vague concept. From a lung cancer perspective this commentary reviews the current knowledge on cancer cachexia mechanisms and identifies specific ways of clinical management regarding food intake, systemic inflammation, and muscular dysfunction. Much of what we know comes from preclinical studies. More translational research is needed for a future cancer cachexia screening tool to guide clinicians, and here possible variables for a cancer cachexia screening tool are considered.

Improved metabolic regulation is associated with retinoblastoma protein gene haploinsufficiency in mice

2015 ◽  
Vol 308 (2) ◽  
pp. E172-E183 ◽  
Author(s):  
Petar D. Petrov ◽  
Joan Ribot ◽  
Andreu Palou ◽  
M. Luisa Bonet
Keyword(s):  
Adipose Tissue ◽  
Body Fat ◽  
White Adipose Tissue ◽  
Metabolic Regulation ◽  
Retinoblastoma Protein ◽  
Acid Oxidation ◽  
Mature Adult ◽  
Adult Age ◽  
Enhanced Sensitivity ◽  
Partial Deficiency

Retinoblastoma protein (pRb) is involved in the control of energy metabolism, and its inactivation protects mice against high-fat diet-induced diabesity. Here, we tested the hypothesis that partial deficiency in the Rb gene could confer metabolic advantages in front of acute challenges to metabolism and as mice age on a regular diet. Rb haploinsufficient (Rb+/−) mice and wild-type (WT) littermates were studied from weaning and characterized at 1.5–2.5 mo of age (young adults) and 6–7.5 mo of age (mature adults). Whereas no differences in body weight or composition were observed at young age, mature adult Rb+/− mice were leaner than WT littermates, displaying 36% reduced body fat content. At both ages studied, Rb+/− mice displayed improved blood lipids, enhanced sensitivity to the blood glucose-lowering effect of insulin and to the anorectic effect of leptin, and a reduced respiratory exchange ratio, indicative of an increased use of fatty acids as a fuel. Insulin sensitivity and oral fat tolerance were better maintained with age in the Rb+/− than the WT mice. Mature adult Rb+/− mice displayed gene expression changes consistent with increased fatty acid oxidation in white adipose tissue and skeletal muscle and paramount signs of browning in the inguinal white adipose tissue. In conclusion, Rb haploinsufficiency provides metabolic advantages in front of acute metabolic stressors and ameliorates body fat gain and metabolic impairments that normally accompany transition from young to mature adult age.

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