高脂饮食诱导肥胖和游泳运动对小鼠心脏脂质沉积的影响

目的 明确高脂饮食诱导肥胖和游泳运动对小鼠心脏脂质沉积的影响。 方法 C57BL/6J小鼠分为普通饲料组（NC）、高脂饲料诱导肥胖组（DIO）、肥胖低运动组（DIO+LE）、肥胖高运动组（DIO+HE）,DIO+LE小鼠每天自由游泳30分钟;DIO+HE小鼠游泳3×30分钟,间隔15分钟。连续游泳运动4周后,油红O染色检测心脏脂质沉积,RT-qPCR分析基因表达变化,免疫组织染色观察线粒体标记物MTCO2水平变化。 结果 NC小鼠心脏可见少量脂滴,DIO小鼠心肌细胞内脂滴的数量显著减少(P<0.05)。DIO+HE小鼠心肌细胞内脂滴的数量较DIO显著增加(P<0.05)。DIO小鼠心脏中乙酰辅酶A羧化酶1（ACC1）、脂肪酸合酶（FAS）等基因表达较NC组显著下降(P<0.05),肉毒碱棕榈酰转移酶（CPT1和CPT2）、3-磷酸甘油脱氢酶（GPD-1）和甘油激酶（GyK）基因表达较NC显著升高(P<0.05)。DIO+HE进一步增加CPT1和CPT2表达,但是逆转DIO小鼠的GPD-1和GyK升高(P<0.05)。DIO+HE小鼠MTCO2免疫染色较DIO组显著增强(P<0.05)。 结论 单纯高脂饲料诱导的肥胖模型小鼠并未增加心脏脂质沉积,反而出现脂质减少,一定运动量可逆转此种变化。本研究为高脂饮食和运动影响心脏脂质沉积提供了新的认识。     

慢性束缚应激对小鼠胃食管的影响

目的探讨心理应激在胃食管反流病(GERD)发生、发展中的作用,并为束缚应激模型的成功建立提供参考指标。 方法20只雄性SPF级昆明小鼠随机分2组(每组10只),即慢性束缚应激(CRS)组和正常对照(NC)组。CRS组小鼠每天在自制式束缚器中限制活动2 h,其余时间2组小鼠在相同环境中自由饮水摄食,实验持续14 d。实验结束后通过葡萄糖耐量试验(GTT)、胰岛素耐受试验(ITT)、小鼠胃食管组织及血清,检测相关指标确认该模型建立成功与否,同时在光学显微镜下观察胃食管黏膜组织学改变。 结果CRS组小鼠体重增加量为(8.6±3.1)g,明显低于NC组小鼠(12.5±3.0)g,差异有统计学意义(P<0.05);胰岛素耐受试验(ITT)结果显示,CRS组小鼠出现胰岛素抵抗现象;ELISA实验显示CRS组小鼠HPA轴相关激素水平明显高于NC组,差异有统计学意义(P<0.05)。CRS组小鼠胃食管黏膜可见充血、水肿及炎症细胞的浸润。 结论CRS可影响机体,引起GERD相关组织病理学变化。为阐述心理因素在GERD中的作用机制研究提供简单有效并且具有借鉴意义的实验基础。     

棕色脂肪组织特异性基因在抵抗肥胖中作用的研究

目的通过研究高脂饮食诱导肥胖与肥胖抵抗大鼠肩胛间棕色脂肪组织中UCP-1、PGC-1α、Dio-2的表达情况以及电针刺激对肥胖大鼠UCP-1、PGC-1α表达的影响,探讨棕色脂肪组织特异性基因在抵抗肥胖中的作用。方法 40只雄性SD大鼠,按体重随机分为高脂实验组(n=28)和基础对照组(n=12)。分别给予高脂饲料和基础饲料喂养。高脂饮食5周末,将高脂实验组大鼠体重大于基础对照组最大体重者归为饮食诱导肥胖大鼠(DIO),将高脂实验组大鼠体重低于对照组平均体重者归为饮食诱导肥胖抵抗大鼠(DIO-R)。从DIO随机取6只为肥胖组(n=6)与肥胖抵抗组(n=6)、基础对照组(n=6),比较各组大鼠体重、两种脂肪重水平,使用实时荧光定量PCR及Western blot方法比较三组肩胛间棕色脂肪组织中UCP-1、PGC-1α、Dio-2表达水平的差异。在DIO大鼠中再取10只随机分为:肥胖组(Ob组,n=5)、电针刺激组(EA组,n=5)与基础对照组(n=5)以基础饲料适应性喂养1周后,其中EA组选取足三里、三阴交给予电针刺激,每周3次,每次30 min,观察摄食量及体重变化。6周后使用实时荧光定量PCR及Westernblot方法比较3组大鼠棕色脂肪组织中UCP-1、PGC-1α表达水平的差异。结果 DIO组明显高于DIO-R组,DIO-R组大鼠肩胛间棕色脂肪组织重及Dio-2、PGC-1α、UCP-1mRNA表达水平明显高于DIO大鼠(P<0.05)。高脂组大鼠PGC-1α、Dio-2m RNA表达水平均低于对照组大鼠(P<0.05);DIO-R组大鼠UCP-1 mRNA表达水平高于对照组大鼠(P<0.05)。DIO大鼠UCP-1蛋白水平表达低于基础对照组及DIO-R大鼠(P<0.05)。电针刺激6周后,电针刺激组大鼠棕色脂肪组织中UCP-1、PGC-1αmRNA及蛋白水平表达均高于Ob组及对照组(P<0.05)。电针刺激组大鼠体重、摄食量低于肥胖组大鼠(P<0.05)。结论高脂饮食条件下,SD大鼠表现为明显的肥胖易感性差异。饮食诱导肥胖抵抗大鼠棕色脂肪组织重及特异性基因表达升高。电针刺激增加了棕色脂肪组织特异性基因表达,减少摄食量。棕色脂肪组织特异性基因表达在抵抗肥胖中有重要作用。     

不同饲料配方及喂饲方法制备不同胰岛素敏感性大鼠模型的研究

目的使用不同饲料配方及喂饲方法制备具有不同胰岛素敏感性（IS）的大鼠模型方法132只雄性SD大鼠分为3组（对照组、肥胖组、限食组）,使用两种饲料（基础与高脂高能）及两种喂饲方式（自由与限食）喂饲6个月.各组大鼠在喂饲至2个月、4个月、6个月时采用正常血糖、高血浆胰岛素钳夹技术检测IS并进行口服糖耐量试验;同时检测大鼠体重、内脏体脂重量及空腹血浆胰岛素（FIns）水平.结果在此喂饲条件下,各组大鼠IS由高到低依次为：限食组＞对照组＞肥胖组.肥胖组大鼠喂饲2个月时就已出现IS明显减退（55%）和糖耐量受损,并随喂饲时间延长而加重;对照组大鼠喂饲2个月、4个月时IS与糖耐量结果正常,6个月时糖耐量与IS有所减退;限食组大鼠始终保持胰岛素高敏状态,实验结束时,该组大鼠IS分别为对照组和肥胖组的5倍与10倍.三组大鼠的体重、体内脂肪含量及血浆胰岛素水平均有相应的变化.结论本实验采用的不同饲料及喂饲方式可以成功地制备稳定可靠的、具有不同IS的大鼠模型.     

Toll样受体2基因敲除对高脂饮食诱导的肥胖小鼠脂肪组织凋亡的影响

目的分析Toll样受体(TLR)2敲除对高脂饮食诱导的肥胖小鼠脂肪组织凋亡的影响。方法 C57BL/6J小鼠和TLR2基因敲除小鼠各16只,分为两组,给予普通饮食和高脂饮食喂养:正常对照组(NC)、肥胖组(OB)、TLR2基因敲除组(TK)和TLR2基因敲除肥胖组(TO)。16 w后检测各组空腹血糖(FPG),三酰甘油(TG),总胆固醇(TC),低密度脂蛋白(LDL)和高密度脂蛋白(HDL)水平及脂肪组织caspase3活性,bcl2和bax蛋白、mRNA表达量。结果与NC组相比,OB组小鼠脂肪组织caspase3活性升高,bax蛋白和mRNA水平升高,bcl2蛋白和mRNA水平降低;与OB组相比,TO组小鼠脂肪组织caspase3活性降低,bax蛋白和mRNA水平降低,bcl2蛋白和mRNA水平升高。结论 TLR2敲除减轻了高脂饮食诱导的肥胖小鼠脂肪组织的细胞凋亡。     

DIO小鼠袖状胃切除术与改良Roux-en-Y胃旁路术模型建立

目的建立饮食诱导的肥胖型（DIO）小鼠袖状胃切除术（SG）与改良Roux-en-Y胃旁路术（RYGB）模型,为代谢外科治疗肥胖伴2型糖尿病（T2DM）机制研究提供动物模型。 方法选取体质量（BMI）、周龄等均无明显差异的13周育龄雄性DIO小鼠,小鼠平均体质量（33.69±2.25）g,平均空腹血糖（11.66±1.52）mmol/L。显微镜下成功建立小鼠SG组（n=7）、改良RYGB组（n=10）和对照组（n=6）模型。术前及术后第l、2、4、7、14天进行小鼠体重和空腹血糖测量。 结果SG组小鼠存活率为85.71%（6/7）,改良RYGB组存活率为60.00%（6/10）。术后SG组和改良RYGB组小鼠体重进行性下降,而对照组小鼠体重变化不明显。术后第4、7、14天,SG组和改良RYGB组体重水平较对照组显著下降（P<0.05）。两种手术组小鼠术后不同观察时间段空腹血糖水平较对照组有明显的差异性（P<0.05）。 结论本研究成功建立DIO小鼠显微镜下袖状胃切除术与改良Roux-en-Y胃旁路术模型。通过DIO小鼠建立改良Roux-en-Y胃旁路术和袖状胃切除术小鼠模型是有效和可行的。此模型为代谢外科治疗肥胖伴T2DM机制的研究提供一个更为合理的动物模型。     

饮食调整对非酒精性脂肪肝病的治疗作用及机制

目的:观察饮食调整对SD大鼠非酒精性脂肪肝病(NAFLD)的治疗作用, 并探讨其作用机制.方法:SD大鼠, ♂, 80只, 随机分为8 wk对照组(NG 8 wk组)、12 wk对照组(NG 12 wk组)、8 wk高脂组(HG 8 wk组)、12 wk高脂组(HG 12 wk组)及饮食调整组(DG组)各16只. NG组喂饲普通饲料, HG组喂饲高脂饲料,DG组喂饲高脂饲料, 8 wk后改普通饲料继续喂饲4 wk. 正糖高胰岛素钳夹实验检测葡萄糖输注率(GIR), 放射免疫法和生化法检测血清及肝匀浆生化指标; Western blot检测肝组织c-jun氨基末端激酶(JNK)1、胰岛素受体底物-1(IRS-1)、胰岛素受体底物-1丝氨酸307磷酸化(phospho-IRS-1Ser307, p-IRS-1Ser307)的表达.结果:HG组与同期NG组大鼠比较, 体质量、肝指数、血清ALT、AST、TG、TC、FFAs、FIns、TNF-α及肝匀浆TG、TC、FFAs、MDA均明显升高(P <0.05或0.01), 肝匀浆SOD降低(t = 4.88, 7.92); GIR降低(均P <0.05); 肝组织JNK1蛋白表达、p-IRS1Ser307水平增高(t =4.39, 5.81; 4.60, 6.48), JNK1蛋白表达强度与胰岛素抵抗呈正相关; HG 12 wk组和HG 8 wk组大鼠上述各项指标比较, 差异均具有统计学意义(P <0.05或0.01); 随着喂养时间的延长,HG组大鼠肝细胞脂肪变性明显加重; 而DG组大鼠的上述各项指标均得到明显改善, 但仍未达到同期NG组大鼠水平(均P <0.05).结论:高脂饮食喂养8 wk及12 wk分别能够构建SD大鼠NAFLD及NASH模型, 仅恢复正常饮食对于高脂饮食诱导的NAFLD有一定的治疗作用.     

高脂诱导肥胖大鼠血清游离脂肪酸与血糖代谢的相关性

目的研究高脂诱导肥胖大鼠血清游离脂肪酸与血糖代谢的相关性。方法选择SD大鼠36只作为研究动物并随机分为高脂饮食组和普通饮食组,高脂饮食组给予高脂饲料喂养,正常饮食组给予普通饲料喂养,4 w、8 w、12 w后采集血清并测定游离脂肪酸(FFA)、空腹血糖(FPG)、空腹胰岛素(FINS),计算胰岛素抵抗指数(HOMA-IR)、胰岛素分泌指数(HOMA-β)。结果喂养8 w、12 w时,高脂饮食组大鼠体重明显高于普通饮食组(t=3.120,4.528,均P0.05);喂养4 w、8 w、12 w时,高脂饮食组大鼠血清中FFA均明显高于普通饮食组(t=5.995,8.175,13.942,均P0.05);两组FPG比较无统计学意义(t=0.869,0.496,0.827,均P0.05),高脂饮食组血清FINS、HOMA-IR、HOMA-β均明显高于普通饮食组(t=5.152,7.411,6.638;5.868,9.770,8.858;2.517,2.890,4.390,均P0.05);血清FFA含量与FINS、HOMA-IR、HOMA-β呈正相关(r=0.724,0.668,0.637,均P0.05)。结论高脂诱导肥胖大鼠的血清FFA含量显著升高且存在胰岛素抵抗和高胰岛素血症,FFA含量与胰岛素抵抗程度具有良好的相关性。     

外源性活性肽spexin调控脂肪组织胰岛素抵抗的机制研究

目的探讨外源性活性肽spexin调节脂肪组织胰岛素抵抗的作用及机制。方法高脂饮食16周诱导肥胖模型(DIO)小鼠和糖尿病模型(db/db)小鼠, 分别腹腔注射spexin(50 μg/kg), 连续给药3周, 对照组给予等体积生理盐水。给药结束后, 分析各组小鼠体重、内脏脂肪重量及血浆生化指标。实时荧光定量PCR检测脂肪组织Krüppel样转录因子9(KLF9)、过氧化物酶体增殖物激活受体γ共激活因子-1α(PGC-1α)及葡萄糖转运蛋白4(GLUT4)基因水平;Western印迹法检测脂肪组织KLF9、PGC-1α、GLUT4及p-p38/p38蛋白水平。结果与DIO模型对照组小鼠相比, spexin给药组小鼠体重和脂肪均明显减少(P=0.043和P<0.001), 血糖、胰岛素及HOMA-IR均显著下降(P<0.001、P=0.008和P<0.001), 葡萄糖耐量和胰岛素耐量水平均显著提高(P=0.006和P=0.002);与db/db模型对照组小鼠相比, spexin给药组小鼠的体重和脂肪均明显减少(均P<0.001), 血糖、胰岛素及HOMA-IR均显...     

白细胞介素-22在猪螺杆菌感染的肥胖小鼠胃黏膜相关淋巴组织中的表达及意义

目的探讨白细胞介素-22(IL-22)在猪螺杆菌(Helicobacter suis,H.suis)感染的肥胖小鼠胃黏膜相关淋巴组织(mucosa associated lymphoid tissue,MALT)中的表达及意义。方法 40只雌性C57BL/6小鼠随机分为4组,每组10只,即正常对照组(NC组)、高脂饮食组(HFD组)、感染组(HS组)与感染+高脂饮食组(HS+HFD组)。NC组与HS组给予普通饮食,HFD组与HS+HFD组自感染后第3周开始给予高脂饮食;差异性饮食24周后处死小鼠(实验过程中无小鼠死亡),取其胃组织行HE染色检测各组小鼠胃黏膜淋巴滤泡的数量与大小;Real-time PCR检测各组小鼠胃黏膜IL-22及其受体IL-22R1与B细胞趋化因子CXCL13 mRNA表达水平。结果 H.suis感染可诱导小鼠胃黏膜淋巴滤泡的形成;与HS组相比,HS+HFD组小鼠胃黏膜淋巴滤泡的数量与大小明显增加,胃黏膜IL-22、CXCL13 mRNA表达水平也明显增加。结论高脂饮食诱导的肥胖可促进H.suis感染后胃MALT的形成,其机制可能与肥胖时胃黏膜中IL-22的表达上调有关。     

The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance

BACKGROUND/AIMS: Non-alcoholic steatohepatitis is an important disease whose pathophysiology remains incompletely understood, although in humans a strong association with insulin resistance exists. Mice fed a methionine-choline deficient (MCD) diet develop steatohepatitis, however the influence of insulin in this model is unknown. METHODS: Male FVB/NJ mice were fed the MCD, MCD control or chow diet for 10 or 28 days. Fasting glucose, ALT, triglyceride and insulin was measured. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed followed by quantitative insulin sensitivity check index (QUICKI) determination. RESULTS: ALT levels were significantly higher in the MCD group. Fasting glucose was 81+/-5 mg/dl in MCD diet fed mice, compared to MCD controls (196+/-46 mg/dl) and chow (199+/-15 mg/dl) (P<0.0001). During GTT and ITT, the effect of glucose administration on blood glucose was dampened, and the insulin effect more pronounced in the MCD group (P=0.026 and P<0.001). QUICKI in MCD fed mice was significantly higher than in the chow fed mice. CONCLUSIONS: GTT, ITT and QUICKI confirmed the absence of insulin resistance in the MCD fed mice. This model causes fibrosing steatohepatitis and may help delineate the non-insulin resistant mechanisms involved in human steatohepatitis.     

代谢相关性脂肪性肝病小鼠不同高脂饮食时期血糖水平和肠道菌群变化动态分析

目的 探讨在不同高脂饮食喂养时期代谢相关性脂肪性肝病(MAFLD)小鼠血糖水平和肠道菌群的动态变化.方法 采用高脂食物饲喂12只C57BL/6小鼠24周,分别在喂养0周、8周、16周和24周行葡萄糖耐量试验(GTT)和胰岛素耐受试验(ITT).采集小鼠粪便进行16sRNA检测,分析肠道细菌结构和肠道菌群多样性的变化.结...     

腺苷酸活化蛋白激酶对糖尿病大鼠非酒精性脂肪性肝病的影响

目的 观察腺苷酸活化蛋白激酶（AMPK）在糖尿病大鼠肝脏的表达,探讨其在非酒精性脂肪性肝病（NAFLD）发病中的作用.方法 40只雄性SD大鼠随机分为正常对照（NC）组、饮食诱导肥胖（DIO）组、糖尿病（DM）组.采用Western-blot方法测定肝脏AMPK蛋白表达;HE染色后观察肝脏形态学变化.结果 DIO组血清FIns、HOMA-IR及肝脏TG含量均较NC组升高;DM组FIns、HOMA-IR较NC组及DIO组升高;DIO组肝AMPK蛋白较NC组降低（P＜0.05）;DM组肝AMPK蛋白表达较DIO组降低（P＜0.05）;DM组肝脏磷酸化腺苷酸活化蛋白激酶（p-AMPK）表达较NC组降低（P＜0.01）.结论 AMPK可能参与了肥胖及糖尿病大鼠NAFLD的发生发展.     

In vivo changes in central and peripheral insulin sensitivity in a large animal model of obesity

Obesity disrupts homeostatic energy balance circuits leading to insulin resistance. Here we examined in vivo peripheral and central insulin sensitivity, and whether central insensitivity in terms of the voluntary food intake (VFI) response occurs within the hypothalamus or at blood-brain transfer level, during obesity and after subsequent weight loss. Sheep with intracerebroventricular (i.c.v.) cannulae were fed complete diet for 40 wk ad libitum (obese group) or at control level (controls). Thereafter, obese sheep were food restricted (slimmers) and controls fed ad libitum (fatteners) for 16 wk. Dual-energy x-ray absorptiometry (DEXA) measured total body fat, insulin analyses in blood and cerebrospinal fluid (CSF) assessed blood-brain transfer, i.v. glucose tolerance test (GTT) and insulin tolerance test (ITT) measured peripheral insulin sensitivity, and VFI responses to icv insulin assessed intrahypothalamic sensitivity. Insulinemia was higher in obese than controls; plasma insulin correlated with DEXA body fat and CSF insulin. Insulinemia was higher in fatteners than slimmers but ratio of CSF to plasma insulin correlated only in fatteners. Plasma glucose baseline and area under the curve were higher during GTT and ITT in obese than controls and during ITT in fatteners than slimmers. GTT and ITT glucose area under the curve correlated with DEXA body fat. VFI decreased after i.c.v. insulin, with response magnitude correlating negatively with DEXA body fat. Overall, insulin resistance developed first in the periphery and then within the brain, thereafter correlating with adiposity; central resistance in terms of VFI response resulted from intrahypothalamic insensitivity rather than impaired blood-brain transfer; modest weight loss improved peripheral but not central insulin sensitivity and induced central hypoinsulinemia.     

胃食管反流病患者口腔pH值变化的探讨

目的比较健康人与胃食管反流病（GERD）患者不同口腔黏膜的pH值及唾液缓冲能力。 方法采用二点测试法对30例胃食管反流病患者使用精密pH试纸测试不同口腔黏膜的pH值及唾液缓冲能力,并与34名健康人作对照。 结果GERD组平均pH值为6.38±0.33,显著低于对照组7.11±0.17,GERD组唾液缓冲能力3.37±0.29也显著低于对照组5.07±0.23。GERD组不同时间的口腔pH值之间存在差异,上午9: 00~11: 00口底黏膜的pH值最低,下午2: 30~4: 30硬腭黏膜pH值最高。 结论胃食管反流患者口腔呈酸性,应根据患者口腔具体情况合理用药,纠正口腔pH值异常,以预防口腔并发症的发生。     

Counterintuitive effects of double-heterozygous null melanocortin-4 receptor and leptin genes on diet-induced obesity and insulin resistance in C57BL/6J mice

Circulating levels of leptin correlate with food intake and adiposity. A decline in serum leptin associated with calorie restriction instigates behavioral and metabolic adaptation, increasing appetite and conserving energy. Brain melanocortin-4 receptors (Mc4rs) are important mediators of leptin's effects on appetite and energy expenditure. Because subtle changes in function associated with heterozygous null mutations for either the Leptin (Lep-HET) or Mc4r genes (Mc4r-HET) increase adiposity, we tested the hypothesis that combined heterozygous mutations (Dbl-HET) would severely exacerbate diet-induced obesity (DIO) and insulin resistance in C57BL/6J mice. Serum leptin levels were lower as a function of adiposity in heterozygous Leptin mutants (Lep-HET, Dbl-HET) matched with mice homozygous for the wild-type (WT) Lep gene (Mc4r-HET). Evidence for an additive interaction on adiposity in Dbl-HET mice maintained on a low-fat diet was observed at 10 wk of age. Male but not female mice developed DIO and insulin resistance on a high-fat diet. Compared with WT mice, DIO was more severe in Mc4r-HET but not Lep-HET mice, regardless of sex. However, the response of male and female Dbl-HET mice was different, with males being less and females being more responsive relative to Mc4r-HET. Glucose tolerance of Dbl-HET mice was not significantly different from WT mice in either sex. These results show a complex interaction between the Leptin and Mc4r genes that is influenced by age, gender, and diet. Remarkably, while heterozygous Lep mutations initially exacerbate obesity, in situations of severe obesity, reduced leptin levels may act oppositely and have beneficial effects on energy homeostasis.     

Role of fat amount and type in ameliorating diet-induced obesity: insights at the level of hypothalamic arcuate nucleus leptin receptor, neuropeptide Y and pro-opiomelanocortin mRNA expression

Aims: Dietary fatty acid profile, independent of caloric percent of fat, is a major regulator of body adiposity. This study examined the effects of dietary fat amount and types on fat storage and hypothalamic gene expression in the mouse model of chronic diet‐induced obesity. Methods: The dietary interventions were in twofold: (1) the obesity was induced by a 13‐week obesogenic fat diet compared with a low‐fat (LF) diet, and (2) the reversibility was tested by using high n‐3 polyunsaturated fat (PUFA) and LF diets. Fifty‐four C57Bl/6 mice were fed a high‐fat (59% in kcal) diet for 13 weeks and then classified as diet‐induced obese (DIO) or diet‐resistant (DR) mice according to upper and lower tertiles of body weight gain. The DIO mice were then subdivided into three groups for a 6‐week secondary dietary intervention. Two of the groups were switched to either a high n‐3 PUFA (DIO‐n3) or a low‐fat (10% in kcal, DIO‐LF) diet, whereas the third (controls) and DR mice continued on the initial high‐fat diet. Food efficiency was calculated as weekly body weight gain per gram of food intake. Results: After switching the DIO mice to the n‐3 PUFA or LF diet, their body weights were reduced to the level of the DR and LF mice. The food efficiencies were, from the highest to lowest, in the order: DIO > LF > DR > DIO‐LF > DIO‐n3. Using quantitative in situ hybridization, we found that the DIO mice had higher levels of leptin receptor (LR, +290%, p < 0.005) and neuropeptide Y (NPY, +25%, p < 0.05) mRNA expression in the hypothalamic arcuate nucleus (Arc) than the DR mice, whereas the level of pro‐opiomelanocortin (POMC) mRNA expression was significantly reduced (?45%, p < 0.01). All effects that were essentially returned to DR levels by the change to the n‐3 PUFA diet and, with the exception of a failure to normalize Arc NPY mRNA levels, by the change to LF diet. Conclusions: Taken together, the present results show that both change in level and quality of dietary fat can potently alter hypothalamic neuropeptide expression and result in effective amelioration of diet‐induced obesity. Interestingly, the n‐3 PUFA diet when fed to already obese mice produced a pattern of hypothalamic gene expression similar to that in obesity resistant (DR) mice. It remains to be determined if the effects of n‐3 fatty acids on brain neuropeptide gene expression are direct or indirect.