Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

Zhou, Hong; Lei, Xinnuo; Benson, Tyler W; Mintz, James D.; Xu, Xiaojing; Harris, Ruth B. S.; Weintraub, Neal L.; Wang, Xiaoling; Chen, Weiqin

doi:10.1194/jlr.m060244

Cited by 35 publications

(42 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reduced TG level and excessive FAO identified in Bscl2 -/hearts are consistent with the role of BSCL2 in TG turnover and FAO, as reported in BSCL2-deleted adipocytes (44,58). BSCL2 deletion in differentiating adipocytes causes unbridled cAMP/PKA signaling, which recruits more ATGL to lipid droplets to stimulate lipid catabolism (23).…”

Section: Discussionsupporting

confidence: 86%

Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy

Zhou¹,

Lei²,

Yan³

et al. 2019

JCI Insight

Self Cite

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 86%

Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy

Zhou¹,

Lei²,

Yan³

et al. 2019

JCI Insight

Self Cite

View full text Add to dashboard Cite

“…Tissues and cells were homogenized and lysed in lysis buffer as previously described (34). The protein concentration was determined by BCA protein assay (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

“…For fatty acid oxidation (FAO), D6 brown adipocytes were incubated with 800 l of Krebs-Ringer bicarbonate-HEPES (KRBH) plus 2% BSA buffer and 5.5 mM glucose, 300 M palmitic acid, and a final concentration of 0.4 Ci of [1-14 C]palmitic acid (Perkin-Elmer Life Sciences)/ml in six-well culture plates with hydroamine-soaked filter paper fixed on the lid, followed by incubation at 37°C for 2 h. Then, 500 l of 1 M perchloric acid was injected to release the 14 CO 2 , followed by further incubation at 37°C for 1 h. The 14 CO 2 released was measured by scintillation counting of the filter paper. FAO using BAT homogenates was assayed as previously detailed (34,45).…”

Section: Methodsmentioning

confidence: 99%

“…Bscl2-deficient white preadipocytes fail to differentiate into white adipocytes due to unbridled cAMP/PKA signaling, causing lipodystrophy (19,21). Notably, deletion of Bscl2 in mature adipose tissues of adult animals also activates cAMP/PKA signaling and induces browning, fat loss, and obesity resistance (34). cAMP/ PKA signaling is required for sympathetic nervous system (SNS)-induced BAT thermogenesis through norepinephrine-stimulated ␤-adrenergic receptors (AR) (1), but whether this signaling pathway is involved in brown adipogenesis and perinatal BAT development is unclear.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is Not Required for Brown Adipogenesis but Regulates Brown Adipose Tissue Development and Function

Zhou

Black

Benson

et al. 2016

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

Brown adipose tissue (BAT) plays a unique role in regulating whole-body energy homeostasis by dissipating energy through thermogenic uncoupling. Berardinelli-Seip congenital lipodystrophy (BSCL) type 2 (BSCL2; also known as seipin) is a lipodystrophy-associated endoplasmic reticulum membrane protein essential for white adipocyte differentiation. Whether BSCL2 directly participates in brown adipocyte differentiation, development, and function, however, is unknown. We show that BSCL2 expression is increased during brown adipocyte differentiation. Its deletion does not impair the classic brown adipogenic program but rather induces premature activation of differentiating brown adipocytes through cyclic AMP (cAMP)/protein kinase A (PKA)-mediated lipolysis and fatty acid and glucose oxidation, as well as uncoupling. cAMP/PKA signaling is physiologically activated during neonatal BAT development in wild-type mice and greatly potentiated in mice with genetic deletion of Bscl2 in brown progenitor cells, leading to reduced BAT mass and lipid content during neonatal brown fat formation. However, prolonged overactivation of cAMP/PKA signaling during BAT development ultimately causes apoptosis of brown adipocytes through inflammation, resulting in BAT atrophy and increased overall adiposity in adult mice. These findings reveal a key cellautonomous role for BSCL2 in controlling BAT mass/activity and provide novel insights into therapeutic strategies targeting cAMP/PKA signaling to regulate brown adipocyte function, viability, and metabolic homeostasis.

show abstract

“…To study the function of Seipin, genetic models were established in different organisms, including yeast, fly, and mouse, and in human cells (Szymanski et al , ; Cui et al , ; Fei et al , ; Tian et al , ). As a transmembrane protein residing in the endoplasmic reticulum (ER) and in the vicinity of lipid droplet (LD) budding sites, Seipin has been shown to be involved in LD formation (Szymanski et al , ; Wang et al , ), phospholipid metabolism (Fei et al , , ), lipolysis (Zhou et al , , ), and ER calcium homeostasis (Bi et al , ). As a result of the functional studies in these models, several factors that interact with Seipin protein were identified, such as the phosphatidic acid phosphatase lipin, 14‐3‐3β, and glycerol‐3‐phosphate acyltransferase (GPAT; Sim et al , ; Yang et al , ; Talukder et al , ; Pagac et al , ).…”

Section: Introductionmentioning

confidence: 99%

Seipin regulates lipid homeostasis by ensuring calcium‐dependent mitochondrial metabolism

et al. 2018

View full text Add to dashboard Cite

, the gene that causes Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), is important for adipocyte differentiation and lipid homeostasis. Previous studies in revealed that Seipin promotes ER calcium homeostasis through the Ca-ATPase SERCA, but little is known about the events downstream of perturbed ER calcium homeostasis that lead to decreased lipid storage in mutants. Here, we show that glycolytic metabolites accumulate and the downstream mitochondrial TCA cycle is impaired in mutants. The impaired TCA cycle further leads to a decreased level of citrate, a critical component of lipogenesis. Mechanistically, Seipin/SERCA-mediated ER calcium homeostasis is important for maintaining mitochondrial calcium homeostasis. Reduced mitochondrial calcium in mutants affects the TCA cycle and mitochondrial function. The lipid storage defects in mutant fat cells can be rescued by replenishing mitochondrial calcium or by restoring the level of citrate through genetic manipulations or supplementation with exogenous metabolites. Together, our results reveal that Seipin promotes adipose tissue lipid storage via calcium-dependent mitochondrial metabolism.

show abstract

Berardinelli-Seip congenital lipodystrophy 2 regulates adipocyte lipolysis, browning, and energy balance in adult animals

Cited by 35 publications

References 75 publications

Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy

Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy

Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is Not Required for Brown Adipogenesis but Regulates Brown Adipose Tissue Development and Function

Seipin regulates lipid homeostasis by ensuring calcium‐dependent mitochondrial metabolism

Contact Info

Product

Resources

About