Seipin deficiency alters brown adipose tissue thermogenesis and insulin sensitivity in a non-cell autonomous mode

Abstract

Loss-of-function mutations in BSCL2 are responsible for Berardinelli-Seip congenital lipodystrophy, a rare disorder characterized by near absence of adipose tissue associated with insulin resistance. Seipin-deficient (Bscl2−/−) mice display an almost total loss of white adipose tissue (WAT) with residual brown adipose tissue (BAT). Previous cellular studies have shown that seipin deficiency alters white adipocyte differentiation. In this study, we aimed to decipher the consequences of seipin deficiency in BAT. Using a brown adipocyte cell-line, we show that seipin knockdown had very little effect on adipocyte differentiation without affecting insulin sensitivity and oxygen consumption. However, when submitted to cold acclimation or chronic β3 agonist treatment, Bscl2−/− mice displayed altered thermogenic capacity, despite several signs of BAT remodeling. Under cold activation, Bscl2−/− mice were able to maintain their body temperature when fed ad libitum, but not under short fasting. At control temperature (i.e. 21 °C), fasting worsened Bscl2−/− BAT properties. Finally, Bscl2−/− BAT displayed obvious signs of insulin resistance. Our results in these lipodystrophic mice strongly suggest that BAT activity relies on WAT as an energetic substrate provider and adipokine-producing organ. Therefore, the WAT/BAT dialogue is a key component of BAT integrity in guaranteeing its response to insulin and cold-activated adrenergic signals.

Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease

“…Due to the critical role of PPARγ in brown adipogenesis, PPARγ-FKO mice lack BAT, whist in IR-FKO mice, BAT and any residual WAT will be insensitive to insulin. Previous studies have reported that Bscl2 is not required for brown adipocyte differentiation or development [43] , [44] . Consistent with this, Ad-B2 (−/−) mice developed interscapular BAT, albeit with modestly reduced mass, altered gene expression and lipid droplet morphology.…”

“…Consistent with this, Ad-B2 (−/−) mice developed interscapular BAT, albeit with modestly reduced mass, altered gene expression and lipid droplet morphology. Moreover, seipin-deficient brown adipocytes are not inherently insulin resistant, although they may become so indirectly in global seipin knockout mice [44] . Hence, preservation of BAT, and insulin sensitivity in BAT and residual WAT, may at least partly explain why Ad-B2 (−/−) mice do not develop the overt metabolic disease seen in PPARγ-FKO and IR-FKO mice.…”

Exploring Seipin: From Biochemistry to Bioinformatics Predictions

“…Indeed, deletion of seipin during mouse BAT adipogenesis is not sufficient to impair the whole process [ 78 ]. In spite of this, mouse fully differentiated BAT with BSCL2 gene deletion displayed altered thermogenic capacity and some insulin resistance [ 79 ].…”

The collaborative work of droplet assembly

“…In general, these animals phenocopy the human disease in the lack of white adipose tissue, although the degree of lipodystrophy is less severe than in humans. In mammals brown adipose is less severely affected, and recent studies indicate that the developmental pathway is near normal; rather, seipin-deficient animals prematurely activate PKA-dependent lipolysis, display apoptosis and atrophy of the tissue, and have defects in acclimation to cold temperatures under certain circumstances [33, 34]. …”