Altered Brain Cholinergic and Synaptic Markers in Obese Zucker Rats

The association between obesity and loss of cognitive performance has been recognized. Although there are data regarding the metabolic alterations in obese conditions and the development of neuroinflammation, no clear evidence concerning obesity-related cholinergic and synaptic impairments in the frontal cortex and hippocampus has been reported yet. Here, we investigate different cholinergic and synaptic markers in 12-, 16-, and 20-week-old obese Zucker rats (OZRs) compared with lean littermate rats (LZRs), using immunochemical and immunohistochemical analysis. Consequently, OZRs showed body weight gain, hypertension, and dysmetabolism. In 20-week-old OZRs, the reduction of vesicular acetylcholine transporter (VAChT) and alpha7 nicotinic acetylcholine receptors (α7nAChR) occurred both in the frontal cortex and in the hippocampus, suggesting a cognitive dysfunction due to obesity and aging. Among the muscarinic receptors analyzed, the level of expression of type 1 (mAChR1) was lower in the hippocampus of the older OZRs. Finally, we showed synaptic dysfunctions in OZRs, with a reduction of synaptophysin (SYP) and synaptic vesicle glycoprotein 2B (SV2B) in 20-week-old OZRs, both in the frontal cortex and in the hippocampus. Taken together, our data suggest specific alterations of cholinergic and synaptic markers that can be targeted to prevent cognitive deficits related to obesity and aging.

Intact renal afferent arteriolar autoregulatory responsiveness in db/db mice

The db/ db mouse is a genetic model of type 2 diabetes that exhibits progressive renal disease. Obesity, hyperglycemia, and albuminuria (822 ± 365 vs. 28 ± 8 μg/day) are evident in 18-wk-old db/ db compared with db/ m (lean littermate control) mice. Our goal was to determine the blood pressure (BP) phenotype of the db/ db mouse. Mean arterial BP measured in conscious mice by radiotelemetry was not different between db/ db ( n = 9) and db/ m ( n = 12) mice, averaging 113 ± 3 and 112 ± 2 mmHg, respectively. The circadian BP profile of db/ db mice was shifted to the left and exhibited a significant reduction in amplitude compared with db/ m mice. Heart rate (487 ± 9 vs. 542 ± 7 beats/min; P < 0.05) and locomotor activity were significantly reduced in db/ db compared with db/ m mice. We tested the hypothesis that intact afferent arteriole (AA) responsiveness to increases in renal artery pressure (RAP) and angiotensin (ANG) II sensitivity contributes to normal BP in this diabetic model. AA diameters of in vitro blood-perfused juxtamedullary nephrons of db/ db mice (15.7 ± 0.5 μm; n = 38) were significantly larger than those of db/ m mice (12.5 ± 0.4 μm; n = 37). AA responses to increases in RAP and ANG II were not different between kidneys of db/ db and db/ m mice. Significant AA vasoconstriction to 1 nM ANG II was observed in kidneys of db/ db mice (−11 ± 4%), while 10 nM ANG II decreased AA diameter in both groups [ db/ db, −20 ± 4%, ( n = 12); db/ m, −26 ± 4% ( n = 12)]. In summary, AA responses to increases in renal perfusion pressure and ANG II remain intact in db/ db mice. Diabetic renal disease occurs in db/ db mice independently of elevated BP.

Persistently enhanced sensitivity of pancreatic islets from ob/ob mice to PKC-stimulated insulin secretion

Islets from 2-wk-old ob/ob and lean littermate mice were cultured for 4-12 days and then perifused or statically incubated to identify early-onset differences in their regulation of insulin secretion. Islets from these young ob/ob and lean mice increased insulin secretion similarly in response to glucose (10 or 20 mM), whereas responsiveness to glucose plus acetylcholine (10 microM) was greater in islets from ob/ob mice than lean mice. This phenotype-specific effect of acetylcholine was mimicked by phorbol 12-myristate 13-acetate (PMA, 100 nM), a protein kinase C (PKC) agonist, whereas prior downregulation of PKC abolished this phenotype-specific effect of acetylcholine. A high concentration of PMA (1 microM) equally and substantially increased insulin secretion from islets of ob/ob and lean mice, suggesting an enhanced regulatory sensitivity rather than altered responsiveness of the PKC system in islets of ob/ob mice. Addition of BAY K 8644, a Ca2+ channel agonist, to the perifusate enhanced acetylcholine-induced insulin secretion from islets of lean mice to attain the high rates observed in islets from ob/ob mice exposed to acetylcholine alone. We propose that acetylcholine-induced PKC regulation of insulin secretion is altered in islets from ob/ob mice, that this alteration may directly or indirectly involve Ca2+ channels, and that it persists even when islets are cultured for up to 12 days.

Left ventricular function of the isolated, genetically obese rat's heart

We sought to determine if left ventricular (LV) function of the heart from the adult, chronically obese animal is impaired. Hearts from 50 wk-old genetically obese female Zucker rats (624 +/- 13 g) and their lean littermate controls (275 +/- 5 g) were isolated during ether anesthesia, supported metabolically by retrograde aortic perfusion (6 ml/min, 35 degrees C) with physiological solution containing suspended canine erythrocytes (hematocrit, 20%), and the ventricles were paced at 180 beats/min. A distensible, fluid-filled balloon was placed in the LV, and pressure-volume (PV) relationships were obtained. The obese and lean end-diastolic PV curves were not different, and therefore the obese and lean LV chamber compliances were similar. Comparison of the systolic PV relationships demonstrated that the obese rat's heart had a greater pressure-generating capability, which probably was a reflection of its increased LV mass (0.96 +/- 0.03 vs. 0.72 +/- 0.02 g). The calculated average meridional (or circumferential) peak systolic wall stress in the LV of the obese rat's heart, however, was significantly reduced compared with control. This diminished ability to develop systolic stress from the same end-diastolic volumes suggests that the hypertrophied LV of the middle-aged obese rat's heart is dilated or that its contractility is depressed, or both.

Development of obesity in Zucker obese (fafa) rat in absence of hyperphagia

The free-feeding, genetically obese rat is hyperphagic, hyperinsulinemic, and hypertriglyceridemic and has increased fat cell size and number compared to its lean littermate. These experiments demonstrate that, when fafa rats are prevented from expressing hyperphagia throughout life, the complete obese "syndrome" still develops. Furthermore, life-long food restriction does not prevent increased lipoprotein lipase in the fafa rat. The data support the concept that a peripheral metabolic adaptation, probably in lipid metabolism, results in preferential shunting of dietary substrate in the restricted obese rats to adipose tissue with concomitant decreases in other tissues.