Effective energy expenditure is critical for maintaining body weight (BW). However, underlying mechanisms contributing to increased BW remain unknown. We characterized the role of brain angiogenesis inhibitor-3 (BAI3/ADGRB3), an adhesion G-protein coupled receptor (aGPCR), in regulating BW. A CRISPR/Cas9 gene editing approach was utilized to generate a whole-body deletion of the BAI3 gene (BAI3−/−). In both BAI3−/− male and female mice, a significant reduction in BW was observed compared to BAI3+/+ control mice. Quantitative magnetic imaging analysis showed that lean and fat masses were reduced in male and female mice with BAI3 deficiency. Total activity, food intake, energy expenditure (EE), and respiratory exchange ratio (RER) were assessed in mice housed at room temperature using a Comprehensive Lab Animal Monitoring System (CLAMS). While no differences were observed in the activity between the two genotypes in male or female mice, energy expenditure was increased in both sexes with BAI3 deficiency. However, at thermoneutrality (30 °C), no differences in energy expenditure were observed between the two genotypes for either sex, suggesting a role for BAI3 in adaptive thermogenesis. Notably, in male BAI3−/− mice, food intake was reduced, and RER was increased, but these attributes remained unchanged in the female mice upon BAI3 loss. Gene expression analysis showed increased mRNA abundance of thermogenic genes Ucp1, Pgc1α, Prdm16, and Elov3 in brown adipose tissue (BAT). These outcomes suggest that adaptive thermogenesis due to enhanced BAT activity contributes to increased energy expenditure and reduced BW with BAI3 deficiency. Additionally, sex-dependent differences were observed in food intake and RER. These studies identify BAI3 as a novel regulator of BW that can be potentially targeted to improve whole-body energy expenditure.

SummaryStimulus-coupled insulin secretion from β-cells involves the fusion of insulin granules to the plasma membrane (PM) via SNARE complex formation—a cellular process key for maintaining whole-body glucose homeostasis. Optimal insulin secretion depends on how the clamping of SNAREs is released, rendering granules fusogenic. We show that an insulin granule protein synaptotagmin-9 (Syt9) deletion in lean mice increased glucose clearance, random-fed plasma insulin levels, and insulin secretion (in vivo and ex vivo islets) without affecting insulin sensitivity. These outcomes demonstrate that Syt9 has an inhibitory function in insulin secretion. Moreover, Syt9 interacts with PM-Stx1A and soluble Tomosyn-1 proteins to form non-fusogenic complexes between PM and insulin granules, preventing Stx1A-SNARE formation and insulin secretion. Furthermore, Syt9 inhibits SNARE-complex formation by posttranscriptional regulation of Tomosyn-1. We conclude that Syt9 and Tomosyn-1 are endogenous inhibitors that modulate Stx1A availability to determine β-cell secretory capacity.HighlightsSynaptotagmin-9 inhibits biphasic insulin secretion from β-cells.Synaptotagmin-9, syntaxin-1A, and Tomosyn-1 forms a molecular complex that decreases the availability of syntaxin-1A to form SNARE complexes in insulin secretion.Synaptotagmin-9–mediated inhibition of insulin secretion occurs through post-transcriptional regulation of Tomosyn-1.

not available Bangladesh J. Urol. 2021; 24(1): 105-109

Stimulus‐coupled insulin secretion from the pancreatic islet β‐cells involves the fusion of insulin granules to the plasma membrane (PM) via SNARE complex formation—a cellular process key for maintaining whole‐body glucose homeostasis. Less is known about the role of endogenous inhibitors of SNARE complexes in insulin secretion. We show that an insulin granule protein synaptotagmin‐9 (Syt9) deletion in mice increased glucose clearance and plasma insulin levels without affecting insulin action compared to the control mice. Upon glucose stimulation, increased biphasic and static insulin secretion were observed from ex vivo islets due to Syt9 loss. Syt9 colocalizes and binds with tomosyn‐1 and the PM syntaxin‐1A (Stx1A); Stx1A is required for forming SNARE complexes. Syt9 knockdown reduced tomosyn‐1 protein abundance via proteasomal degradation and binding of tomosyn‐1 to Stx1A. Furthermore, Stx1A‐SNARE complex formation was increased, implicating Syt9‐tomosyn‐1‐Stx1A complex is inhibitory in insulin secretion. Rescuing tomosyn‐1 blocked the Syt9‐knockdown‐mediated increases in insulin secretion. This shows that the inhibitory effects of Syt9 on insulin secretion are mediated by tomosyn‐1. We report a molecular mechanism by which β‐cells modulate their secretory capacity rendering insulin granules nonfusogenic by forming the Syt9‐tomosyn‐1‐Stx1A complex. Altogether, Syt9 loss in β‐cells decreases tomosyn‐1 protein abundance, increasing the formation of Stx1A‐SNARE complexes, insulin secretion, and glucose clearance. These outcomes differ from the previously published work that identified Syt9 has either a positive or no effect of Syt9 on insulin secretion. Future work using β‐cell‐specific deletion of Syt9 mice is key for establishing the role of Syt9 in insulin secretion.