Ubc9 deletion in adipocytes causes lipoatrophy in mice

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.

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Inducible brown adipocytes in subcutaneous inguinal white fat: the role of continuous sympathetic stimulation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00033.2014 ◽

2014 ◽

Vol 307 (9) ◽

pp. E793-E799 ◽

Cited By ~ 45

Author(s):

G. Andres Contreras ◽

Yun-Hee Lee ◽

Emilio P. Mottillo ◽

James G. Granneman

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Sympathetic Innervation ◽

Adrenergic Stimulation ◽

Brown Adipocytes ◽

Main Site ◽

Adipose Tissue Depots ◽

Brown Adipose ◽

White Fat

Brown adipocytes (BA) generate heat in response to sympathetic activation and are the main site of nonshivering thermogenesis in mammals. Although most BA are located in classic brown adipose tissue depots, BA are also abundant in the inguinal white adipose tissue (iWAT) before weaning. The number of BA is correlated with the density of sympathetic innervation in iWAT; however, the role of continuous sympathetic tone in the establishment and maintenance of BA in WAT has not been investigated. BA marker expression in iWAT was abundant in weaning mice but was greatly reduced by 8 wk of age. Nonetheless, BA phenotype could be rapidly reinstated by acute β3-adrenergic stimulation with CL-316,243 (CL). Genetic tagging of adipocytes with adiponectin-CreERT2 demonstrated that CL reinstates uncoupling protein 1 (UCP1) expression in adipocytes that were present before weaning. Chronic surgical denervation dramatically reduced the ability of CL to induce the expression of UCP1 and other BA markers in the tissue as a whole, and this loss of responsiveness was prevented by concurrent treatment with CL. These results indicate that ongoing sympathetic activity is critical to preserve the ability of iWAT fat cells to express a BA phenotype upon adrenergic stimulation.

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RIP140 Represses the “Brown-in-White” Adipocyte Program Including a Futile Cycle of Triacyclglycerol Breakdown and Synthesis

Molecular Endocrinology ◽

10.1210/me.2013-1254 ◽

2014 ◽

Vol 28 (3) ◽

pp. 344-356 ◽

Cited By ~ 34

Author(s):

Evangelos Kiskinis ◽

Lemonia Chatzeli ◽

Edward Curry ◽

Myrsini Kaforou ◽

Andrea Frontini ◽

...

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Brown Fat ◽

Minor Role ◽

Wild Type ◽

Uncoupling Protein 1 ◽

Futile Cycle ◽

Brown Adipocytes ◽

White Adipocyte

Abstract Receptor-interacting protein 140 (RIP140) is a corepressor of nuclear receptors that is highly expressed in adipose tissues. We investigated the role of RIP140 in conditionally immortal preadipocyte cell lines prepared from white or brown fat depots. In white adipocytes, a large set of brown fat-associated genes was up-regulated in the absence of RIP140. In contrast, a relatively minor role can be ascribed to RIP140 in the control of basal gene expression in differentiated brown adipocytes because significant changes were observed only in Ptgds and Fabp3. The minor role of RIP140 in brown adipocytes correlates with the similar histology and uncoupling protein 1 and CIDEA staining in knockout compared with wild-type brown adipose tissue (BAT). In contrast, RIP140 knockout sc white adipose tissue (WAT) shows increased numbers of multilocular adipocytes with elevated staining for uncoupling protein 1 and CIDEA. Furthermore in a white adipocyte cell line, the markers of BRITE adipocytes, Tbx1, CD137, Tmem26, Cited1, and Epsti1 were repressed in the presence of RIP140 as was Prdm16. Microarray analysis of wild-type and RIP140-knockout white fat revealed elevated expression of genes associated with cold-induced expression or high expression in BAT. A set of genes associated with a futile cycle of triacylglycerol breakdown and resynthesis and functional assays revealed that glycerol kinase and glycerol-3-phosphate dehydrogenase activity as well as [3H]glycerol incorporation were elevated in the absence of RIP140. Thus, RIP140 blocks the BRITE program in WAT, preventing the expression of brown fat genes and inhibiting a triacylglycerol futile cycle, with important implications for energy homeostasis.

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

Physiology ◽

10.1152/physiol.00038.2020 ◽

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.

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Phosphocholine accumulation and PHOSPHO1 depletion promote adipose tissue thermogenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1916550117 ◽

2020 ◽

Vol 117 (26) ◽

pp. 15055-15065 ◽

Cited By ~ 1

Author(s):

Mengxi Jiang ◽

Tony E. Chavarria ◽

Bingbing Yuan ◽

Harvey F. Lodish ◽

Nai-Jia Huang

Keyword(s):

Adipose Tissue ◽

Negative Regulator ◽

Brown Adipocytes ◽

Diet Induced Obesity ◽

The Metabolic Syndrome ◽

Brown Adipose ◽

Cold Tolerant ◽

Functional Relevance ◽

Hydrolysis Of

Phosphocholine phosphatase-1 (PHOSPHO1) is a phosphocholine phosphatase that catalyzes the hydrolysis of phosphocholine (PC) to choline. Here we demonstrate that the PHOSPHO1 transcript is highly enriched in mature brown adipose tissue (BAT) and is further induced by cold and isoproterenol treatments of BAT and primary brown adipocytes. In defining the functional relevance of PHOPSPHO1 in BAT thermogenesis and energy metabolism, we show that PHOSPHO1 knockout mice are cold-tolerant, with higher expression of thermogenic genes in BAT, and are protected from high-fat diet-induced obesity and development of insulin resistance. Treatment of mice with the PHOSPHO1 substrate phosphocholine is sufficient to induce cold tolerance, thermogenic gene expression, and allied metabolic benefits. Our results reveal a role of PHOSPHO1 as a negative regulator of BAT thermogenesis, and inhibition of PHOSPHO1 or enhancement of phosphocholine represent innovative approaches to manage the metabolic syndrome.

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SIRT3 (Sirtuin-3) Prevents Ang II (Angiotensin II)–Induced Macrophage Metabolic Switch Improving Perivascular Adipose Tissue Function

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315337 ◽

2020 ◽

Author(s):

Tong Wei ◽

Jing Gao ◽

Chenglin Huang ◽

Bei Song ◽

Mengwei Sun ◽

...

Keyword(s):

Adipose Tissue ◽

Angiotensin Ii ◽

Metabolic Phenotype ◽

Inflammasome Activation ◽

Ang Ii ◽

Sirtuin 3 ◽

Metabolic Switch ◽

Brown Adipocytes ◽

Perivascular Adipose Tissue

Objective: Infiltrated macrophages actively promote perivascular adipose tissue remodeling and represent a dominant population in the perivascular adipose tissue microenvironment of hypertensive mice. However, the role of macrophages in initiating metabolic inflammation remains uncertain. SIRT3 (sirtuin-3), a NAD-dependent deacetylase, is sensitive to metabolic status and mediates adaptation responses. In this study, we investigated the role of SIRT3-mediated metabolic shift in regulating NLRP3 (Nod-like receptor family pyrin domain-containing 3) inflammasome activation. Approach and Results: Here, we report that Ang II (angiotensin II) accelerates perivascular adipose tissue inflammation and fibrosis, accompanied by NLRP3 inflammasome activation and IL (interleukin)-1β secretion in myeloid SIRT3 knockout (SIRT3 − / − ) mice. This effect is associated with adipose tissue mitochondrial dysfunction. In vitro studies indicate that the deletion of SIRT3 in bone marrow–derived macrophages induces IL-1β production by shifting the metabolic phenotype from oxidative phosphorylation to glycolysis. Mechanistically, SIRT3 deacetylates and activates PDHA1 (pyruvate dehydrogenase E1 alpha) at lysine 83, and the loss of SIRT3 leads to PDH activity decrease and lactate accumulation. Knocking down LDHA (lactate dehydrogenase A) or using carnosine, a buffer against lactic acid, attenuates IL-1β secretion. Furthermore, the blockade of IL-1β from macrophages into brown adipocytes restores thermogenic markers and mitochondrial oxygen consumption. Moreover, NLRP3 knockout (NLRP3 −/− ) mice exhibited reduced IL-1β production while rescuing the mitochondrial function of brown adipocytes and alleviating perivascular adipose tissue fibrosis. Conclusions: SIRT3 represents a potential therapeutic target to attenuate NLRP3-related inflammation. Pharmacological targeting of glycolytic metabolism may represent an effective therapeutic approach.

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White, Brown, Beige/Brite: Different Adipose Cells for Different Functions?

Endocrinology ◽

10.1210/en.2013-1403 ◽

2013 ◽

Vol 154 (9) ◽

pp. 2992-3000 ◽

Cited By ~ 250

Author(s):

Marta Giralt ◽

Francesc Villarroya

Keyword(s):

Adipose Tissue ◽

Cell Lineage ◽

Precursor Cells ◽

Brown Adipocyte ◽

Brown Adipocytes ◽

White Adipocyte ◽

Brown Adipose ◽

Adult Humans ◽

Adipocyte Cell ◽

Adipose Cells

Brown adipose tissue (BAT) is a major site of nonshivering thermogenesis in mammals. Rodent studies indicated that BAT thermogenic activity may protect against obesity. Recent findings using novel radiodiagnosis procedures revealed unanticipated high activity of BAT in adult humans. Moreover, complex processes of cell differentiation leading to the appearance of active brown adipocytes have been recently identified. The brown adipocytes clustered in defined anatomical BAT depots of rodents arise from mesenchymal precursor cells common to the myogenic cell lineage. They are being called “classical” or “developmentally programmed” brown adipocytes. However, brown adipocytes may appear after thermogenic stimuli at anatomical sites corresponding to white adipose tissue (WAT). This process is called the “browning” of WAT. The brown adipocytes appearing in WAT derive from precursor cells different from those in classical BAT and are closer to the white adipocyte cell lineage. The brown adipocytes appearing in WAT are often called “inducible, beige, or brite.” The appearance of these inducible brown adipocytes in WAT may also involve transdifferentiation processes of white-to-brown adipose cells. There is no evidence that the ultimate thermogenic function of the beige/brite adipocytes differs from that of classical brown adipocytes, although some genetic data in rodents suggest a relevant role of the browning process in protection against obesity. Although the activation of classical BAT and the browning process share common mechanisms of induction (eg, noradrenergic-mediated induction by cold), multiple novel adrenergic-independent endocrine factors that activate BAT and the browning of WAT have been identified recently. In adult humans, BAT is mainly composed of beige/brite adipocytes, although recent data indicate the persistence of classical BAT at some anatomical sites. Understanding the biological processes controlling brown adipocyte activity and differentiation could help the design of BAT-focused strategies to increase energy expenditure and fight against obesity.

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

10.1101/324160 ◽

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.

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Role of Ubiquilins for Brown Adipocyte Proteostasis and Thermogenesis

Frontiers in Endocrinology ◽

10.3389/fendo.2021.739021 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carolin Muley ◽

Stefan Kotschi ◽

Alexander Bartelt

Keyword(s):

Gene Expression ◽

Quality Control ◽

Adipose Tissue ◽

Cold Exposure ◽

Protein Quality ◽

Brown Adipocyte ◽

Brown Adipocytes ◽

Brown Adipose ◽

Shivering Thermogenesis

The acclimatization of brown adipose tissue (BAT) to sustained cold exposure requires an adaptive increase in proteasomal protein quality control. Ubiquilins represent a recently identified family of shuttle proteins with versatile functions in protein degradation, such as facilitating substrate targeting and proteasomal degradation. However, whether ubiquilins participate in brown adipocyte function has not been investigated so far. Here, we determine the role of ubiquilins for proteostasis and non-shivering thermogenesis in brown adipocytes. We found that Ubqln1, 2 and 4 are highly expressed in BAT and their expression was induced by cold and proteasomal inhibition. Surprisingly, silencing of ubiquilin gene expression (one or multiple in combinations) did not lead to aggravated ER stress or inflammation. Moreover, ubiquitin level and proteasomal activity under basal conditions were not impacted by loss of ubiquilins. Also, non-shivering thermogenesis measured by norepinephrine-induced respiration remained intact after loss of ubiquilins. In conclusion, ubiquilin proteins are highly abundant in BAT and regulated by cold, but they are dispensable for brown adipocyte proteostasis and thermogenesis.

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Multifaceted Roles of Beige Fat in Energy Homeostasis Beyond UCP1

Endocrinology ◽

10.1210/en.2018-00371 ◽

2018 ◽

Vol 159 (7) ◽

pp. 2545-2553 ◽

Cited By ~ 9

Author(s):

Carlos Henrique Sponton ◽

Shingo Kajimura

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

Developmental Regulation ◽

Brown Adipocytes ◽

Adipose Tissue Depots ◽

Brown Adipose ◽

Beige Adipocytes ◽

Beige Fat ◽

Adipose Cells

Abstract Beige adipocytes are an inducible form of thermogenic adipose cells that emerge within the white adipose tissue in response to a variety of environmental stimuli, such as chronic cold acclimation. Similar to brown adipocytes that reside in brown adipose tissue depots, beige adipocytes are also thermogenic; however, beige adipocytes possess unique, distinguishing characteristics in their developmental regulation and biological function. This review highlights recent advances in our understanding of beige adipocytes, focusing on the diverse roles of beige fat in the regulation of energy homeostasis that are independent of the canonical thermogenic pathway via uncoupling protein 1.

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Challenging a “Cushy” Life: Potential Roles of Thermogenesis and Adipose Tissue Adaptations in Delayed Aging of Ames and Snell Dwarf Mice

Metabolites ◽

10.3390/metabo10050176 ◽

2020 ◽

Vol 10 (5) ◽

pp. 176 ◽

Cited By ~ 1

Author(s):

Teresa G. Valencak ◽

Tanja Spenlingwimmer ◽

Ricarda Nimphy ◽

Isabel Reinisch ◽

Jessica M. Hoffman ◽

...

Keyword(s):

Adipose Tissue ◽

Laboratory Mouse ◽

Somatotropic Axis ◽

Mouse Mutants ◽

Adipose Tissue Depots ◽

Current State ◽

Brown Adipose ◽

Snell Dwarf ◽

Dwarf Mice

Laboratory mouse models with genetically altered growth hormone (GH) signaling and subsequent endocrine disruptions, have longer lifespans than control littermates. As such, these mice are commonly examined to determine the role of the somatotropic axis as it relates to healthspan and longevity in mammals. The two most prominent mouse mutants in this context are the genetically dwarf Ames and Snell models which have been studied extensively for over two decades. However, it has only been proposed recently that both white and brown adipose tissue depots may contribute to their delayed aging. Here we review the current state of the field and supplement it with recent data from our labs.

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