Dodson Andrew D, Herbertson Adam J, Honeycutt Mackenzie K, Vered Ron, Slattery Jared D, Goldberg Matvey, Tsui Edison, Wolden-Hanson Tami, Graham James L, Wietecha Tomasz A, O'Brien Kevin D, Havel Peter J, Sikkema Carl L, Peskind Elaine R, Mundinger Thomas O, Taborsky Gerald J, Blevins James E
VA Puget Sound Health Care System, Office of Research and Development Medical Research Service, Department of Veterans Affairs Medical Center, Seattle, WA 98108, USA.
Department of Nutrition, University of California, Davis, CA 95616, USA.
Curr Issues Mol Biol. 2024 Oct 15;46(10):11394-11424. doi: 10.3390/cimb46100679.
Recent studies have indicated that hindbrain [fourth ventricle (4V)] administration of the neurohypophyseal hormone, oxytocin (OT), reduces body weight, energy intake and stimulates interscapular brown adipose tissue temperature (T) in male diet-induced obese (DIO) rats. What remains unclear is whether chronic hindbrain (4V) OT can impact body weight in female high fat diet-fed (HFD) rodents and whether this involves activation of brown adipose tissue (BAT). We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of interscapular brown adipose tissue (IBAT) contributes to its ability to activate BAT and reduce body weight in female high HFD-fed rats. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of T and reduction of body weight in DIO rats. We first measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (0.5, 1, and 5 µg ≈ 0.5, 0.99, and 4.96 nmol) to stimulate T in female HFD-fed rats. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) stimulated T similarly between sham rats and denervated rats ( = NS). We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day ≈ 16.1 μg/day) or vehicle infusion to reduce body weight, adiposity and energy intake in female HFD-fed rats (N = 7-8/group). Chronic 4V OT reduced body weight gain (sham: -18.0 ± 4.9 g; denervation: -15.9 ± 3.7 g) and adiposity (sham: -13.9 ± 3.7 g; denervation: -13.6 ± 2.4 g) relative to vehicle treatment ( < 0.05) and these effects were similar between groups ( = NS). These effects were attributed, in part, to reduced energy intake evident during weeks 2 ( < 0.05) and 3 ( < 0.05). To test whether these results translate to other female rodent species, we also examined the effect of chronic 4V infusion of OT on body weight and adiposity in two strains of female HFD-fed mice. Similar to what we found in the HFD-fed rat model, we also found that chronic 4V OT (16 nmol/day) infusion resulted in reduced body weight gain, adiposity and energy intake in female DIO C57BL/6J and DBA/2J mice ( < 0.05 vs. vehicle). Together, these findings suggest that (1) sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and weight loss in female HFD-fed rats and (2) the effects of OT to reduce weight gain and adiposity translate to other female mouse models of diet-induced obesity (DIO).
近期研究表明，向雄性饮食诱导肥胖（DIO）大鼠的后脑[第四脑室（4V）]注射神经垂体激素催产素（OT），可降低体重、减少能量摄入，并刺激肩胛间棕色脂肪组织温度（T）。目前尚不清楚的是，长期向后脑（4V）注射OT是否会影响高脂饮食喂养（HFD）雌性啮齿动物的体重，以及这是否涉及棕色脂肪组织（BAT）的激活。我们推测，OT引起的交感神经系统（SNS）对肩胛间棕色脂肪组织（IBAT）的激活，有助于其在高脂饮食喂养的雌性大鼠中激活BAT并减轻体重。为了验证这一假设，我们确定了破坏IBAT的SNS激活对OT引起的DIO大鼠T刺激和体重减轻的影响。我们首先测量了双侧手术去神经支配IBAT对急性4V OT（0.5、1和5μg≈0.5、0.99和4.96 nmol）刺激高脂饮食喂养雌性大鼠T的能力的影响。我们发现，高剂量的4V OT（5μg≈4.96 nmol）在假手术大鼠和去神经大鼠之间对T的刺激相似（=无显著性差异）。随后，我们测量了双侧手术去神经支配IBAT对长期4V OT（16 nmol/天≈16.1μg/天）或注射载体对高脂饮食喂养雌性大鼠（每组N = 7 - 8只）体重、肥胖和能量摄入的影响。相对于载体处理，长期4V OT降低了体重增加（假手术组：-18.0±4.9 g；去神经组：-15.9±3.7 g）和肥胖（假手术组：-13.9±3.7 g；去神经组：-13.6±2.4 g）（<0.05），且这些影响在各组之间相似（=无显著性差异）。这些影响部分归因于第2周（<0.05）和第3周（<0.05）期间能量摄入的明显减少。为了测试这些结果是否适用于其他雌性啮齿动物物种，我们还研究了长期4V注射OT对两种高脂饮食喂养雌性小鼠品系体重和肥胖的影响。与我们在高脂饮食喂养大鼠模型中发现的结果相似，我们还发现，长期4V OT（16 nmol/天）注射导致高脂饮食诱导肥胖的雌性C57BL/6J和DBA/2J小鼠体重增加、肥胖和能量摄入减少（与载体相比，<0.05）。总之，这些发现表明：（1）对于OT引起的高脂饮食喂养雌性大鼠BAT产热增加和体重减轻，IBAT的交感神经支配并非必要；（2）OT减轻体重增加和肥胖的作用适用于其他饮食诱导肥胖（DIO）的雌性小鼠模型。
