Regulating fatty tissue

Bscl2 plays a role in browning adipose tissue.

Many of us have gone on diets to decrease body fat. But what if you needed to put on fat? People born with Berardinelli–Seip congenital lipodystrophy would do anything to gain just a few pounds. Patients suffering from the disease have mutations in their BSCL2 gene that result in a lack of fatty tissue in the body and a lack of functioning adipoctyes for lipid storage. They develop insulin resistance, accumulate fat in both muscle and the liver, and are prone to type 2 diabetes. Recently, the role of Bscl2 regulation in mature adipocyte maintenance was investigated and the results described in the Journal of Lipid Research.

Two primary forms of adipose tissue are present in the body: white and brown. White adipose tissue, or WAT, mainly functions as energy storage, releasing fatty acids into the bloodstream to feed the body, while brown adipose tissue, or BAT, acts to generate heat by consuming fat stores and is predominant in infants, who cannot shiver in response to cold temperatures. Interestingly, studies have found that WAT can brown, forming beige tissue with increased lipolysis and subsequently lowered lipid content.

Previously, global knockdown of Bscl2 in mice resulted in widespread ablation of WAT, while the remaining white fat demonstrated substantial browning effects. These findings compelled Hongyi Zhou and Weiqin Chen at Georgia Regents University to examine the role that Bscl2 plays in adipose development.

To investigate the effects of Bscl2 on mature adipocyte maintenance, mouse models were generated to knockout Bscl2 specifically in adipose tissues after the mice reached adulthood, thus avoiding complicating factors that would arise in global knockouts during infancy. The body weight, food intake and energy expenditures of the mice (versus a control group) were monitored for 12 weeks after inducing Bscl2 knockout, and the mice also were tested for resistance to insulin and glucose tolerance. Intriguingly, the knockout mice showed decreased body fat, reduced food intake and slightly increased energy expenditure, overall leading to leaner mice, even when placed on a high-fat diet. Insulin resistance was noted as observed in human subjects with BSCL2 mutations, but there was not a decrease in glucose tolerance, presenting incomplete symptoms for type 2 diabetes. Importantly, body WAT mass decreased sharply, and browning was noted in the remaining tissues.

The impact of knocking out Bscl2 on gene expression in BAT and WAT was measured using next-generation RNA sequencing. As expected, genes involved in browning, lipolysis and fatty acid oxidation all were upregulated, establishing a basis for reconnecting Bscl2 with beige cell formation and decreased lipid stores. The RNA sequencing also revealed that ADRB3, a G-protein-coupled adrenergic receptor known to stimulate lipolysis, was downregulated in the knockout mice despite the lean phenotype observed. Based on these findings, Bscl2 and ADRB3 have a complex relationship in maintaining whole-body homeostasis, but Bscl2 has a definitive role in lipolysis and browning of WAT in adult tissues.

This discovery immediately conjures ideas of treatments that could regulate Bscl2 to induce the lean phenotype in obese individuals, but much remains to be discovered regarding the role(s) of Bscl2. Knockout mice fed a high-fat diet showed an increase in liver mass of 130 percent. This likely was due to heightened fatty acid synthesis and could act as a precursor to fatty liver disease, a condition often observed in individuals with mutations in the gene. This emphasizes that selective knockout or knockdown of the gene is unlikely to serve as an effective weight-loss treatment.

Further research is needed to tease apart the detailed mechanism by which Bscl2 regulates WAT formation, browning and lipolysis and how these effects intersect with ADRB3 signaling pathways to regulate energy homeostasis. In particular, the structure of Bscl2 needs to be resolved, as there are no known homologs of the protein, limiting predictions of binding targets or effectors. The key to understanding WAT development and browning lies in elucidating Bscl2 signaling pathways and its interaction partners, which could provide essential information for the future treatment of obesity.

Adam Cornish Adam Cornish teaches advanced placement chemistry, blogs about science and pays too much attention to national politics.