Abstract 136: The Ventromedial Hypothalamic BBSome is Required for Energy Homeostasis and Sympathetic Nerve Traffic Control

Abstract

The BBSome, a protein complex of 8 Bardet-Biedl Syndrome (BBS) protein including BBS1, has emerged as an important regulator of metabolic and cardiovascular function. We previously demonstrated that conditional disruption of the BBSome, by deleting the Bbs1 gene, throughout the nervous system leads to obesity in mice. The ventromedial hypothalamus (VMH) play a key role in energy balance, but the contribution of the BBSome in the VMH to the control of energy homeostasis is not known. To address this, we specifically ablated the Bbs1 gene in the VMH by crossing the Bbs1 fl/fl mice with mice expressing Cre recombinase selectively in the VMH, driven by the steroidogenic factor 1 promoter (SF1 Cre ). VMH-selective Cre-recombination was verified using td-Tomato reporter mice. Importantly, SF1 Cre /Bbs1 fl/fl mice develop obesity as indicated by the increased (P<0.05) body weight (males: 43±2 vs 34±1 g in controls, and females: 33±2 vs 27±1 at age of 25 weeks) and fat mass (12.4±1 vs. 5.2±1 g). Of note, heterozygous SF1 Cre /Bbs1 fl/wt mice displayed an intermediate obesity phenotype (body weight: males: 39±2g and females: 30±1g). Daily food intake was not different in SF1 Cre /Bbs1 fl/fl mice relative to controls. However, energy expenditure (EE) was lower in SF1 Cre /Bbs1 fl/fl mice (ANCOVA corrected night EE: 0.27±0.06 vs 0.30±0.06 kcal/h in controls, P<0.05). Moreover, SF1 Cre /Bbs1 fl/fl mice exhibited a blunted cooling-induced increase in sympathetic nerve activity (SNA) subserving thermogenic brown adipose tissue (BAT), although basal BAT SNA activity was not different. Next, we assessed the consequence of SF1 neuron-specific Bbs1 gene deletion on SNA subserving cardiovascular beds. SF1 Cre /Bbs1 fl/fl mice displayed a modest, but significant increase in renal SNA (49±24%, P=0.03) and splanchnic SNA (85±18%, P<0.05), but not lumbar SNA (11±9%, P=0.14). Blood pressure, recoded under anesthesia, was not different in SF1 Cre /Bbs1 fl/fl mice relative to controls (P=0.2). Radiotelemetry measurement of blood pressure in SF1 Cre /Bbs1 fl/fl and control mice is under way. These findings highlight the importance of the VMH BBSome for the regulation of energy homeostasis and sympathetic nerve outflow.