Improvements in hippocampal-dependent memory and microglial infiltration with calorie restriction and gastric bypass surgery, but not with vertical sleeve gastrectomy.

BACKGROUND: Much recent evidence suggest that obesity and related comorbidities contribute to cognitive decline, including the development of non age-related dementia and Alzheimer's disease. Obesity is a serious threat to public health, and few treatments offer proven long-term weight loss. In fact, bariatric surgery remains the most effective long-term therapy to reduce weight and alleviate other aspects of the metabolic syndrome (MetS). Unlike the demonstrated benefits of caloric restriction to prevent weight gain, few if any studies have compared various means of weight loss on central nervous system function and hippocampal-dependent cognitive processes. DESIGN AND RESULTS: Our studies comprise the first direct comparisons of caloric restriction to two bariatric surgeries (Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG)) on cognitive function. Weight loss following caloric restriction, RYGB and VSG was associated with generalized improvements in metabolic health and hippocampal-dependent learning, as measured in the radial arm maze and spontaneous alternation tests. However, VSG-treated rats exhibited deficits on spatial learning tasks in the Morris water maze. In addition, whereas VSG animals had elevated hippocampal inflammation, comparable to that of obese controls, RYGB and calorie-restricted (pair-fed, PF) controls exhibited an amelioration of inflammation, as measured by the microglial protein ionized calcium binding adaptor molecule 1 (IBA1). We also assessed whether GHR (ghrelin) replacement would attenuate hippocampal inflammation in VSG, as post-surgical GHR levels are significantly reduced in VSG relative to RYGB and PF rats. However, GHR treatment did not attenuate the hippocampal inflammation. CONCLUSION: Although VSG was comparably effective at reducing body weight and improving glucose regulation as RYGB, VSG did not appear to confer an equal benefit on cognitive function and markers of inflammation.

Angiotensin-converting enzyme inhibition reverses diet-induced obesity, insulin resistance and inflammation in C57BL/6J mice.

AIM: Angiotensin-converting enzyme (ACE) inhibition can reduce the body weight of mice maintained on a high-fat diet. The current study examined the effect of the ACE inhibitor, captopril (CAP), on the reversal of diet-induced obesity (DIO), insulin resistance and inflammation in mice. MATERIALS AND METHODS: DIO was produced in C57BL/6J male mice (n=30) by maintaining animals on a high-fat diet (w/w 21% fat) for 12 weeks. During the subsequent 12-week treatment period, the animals were allowed access to the high-fat diet and either water containing CAP (0.05 mg ml(-1)) or plain tap water (CON, control). RESULTS: From the first week of treatment, food intake and body weight decreased in CAP-treated mice compared with CON mice. Both peripheral insulin sensitivity and hepatic insulin sensitivity were improved in CAP-treated mice compared with CON mice. CAP-treated mice had decreased absolute and relative liver and epididymal fat weights compared with CON mice. CAP-treated mice had higher plasma adiponectin and lower plasma leptin levels than CON mice. Relative to CON mice, CAP-treated mice had reduced adipose and skeletal muscle monocyte chemoattractant protein 1 (MCP-1), adipose interleukin-6 (IL-6), toll-like receptor 4 (TLR4) and uncoupling protein 2 (UCP2) mRNA expressions. Furthermore, CAP-treated mice had increased peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), long chain acyl-CoA dehydrogenase (LCAD), hormone sensitive lipase (HSL) and decreased lipoprotein lipase (LPL) mRNA expressions in the liver. CONCLUSION: The results of the current study indicate that in mice with DIO, CAP treatment reduced food intake and body weight, improved insulin sensitivity and decreased the mRNA expression of markers of inflammation. Thus, CAP may be a viable treatment for obesity, insulin resistance and inflammation.

Sodium appetite in adult rats following ω-3 polyunsaturated fatty acid deficiency in early development.

We examined the effect of ω-3 polyunsaturated fatty acid (PUFA) deficiency during development on sodium appetite. Being raised on an ω-3 PUFA deficient diet increased the intake of 0.5M NaCl following furosemide-induced sodium depletion by 40%. This occurred regardless of the diet they were maintained on later in life, and the increased consumption persisted for 3 days. In a second study, animals were administered furosemide and low-dose captopril. Sodium consumption of deficient raised animals was again higher than that of the control raised. Fos immunoreactivity in brain areas associated with sodium appetite and excretion were not influenced by diet. Our findings indicate that inadequate dietary ω-3 PUFA during development results in an exaggerated sodium appetite later in life.

Endocrine and ingestive behavioral responses to fluid deprivation in sheep chronically exposed to ethanol.

Endocrine responses to fluid deprivation/restoration and preference for ethanol solution vs. water were assessed in sheep maintained for 5 months on a 10% ethanol solution as their sole source of fluid. Blood pressure, body weight, plasma composition and hormone levels of the alcohol maintained sheep were all within a normal range, except for high plasma concentrations of ANG II and ALDO. During fluid deprivation, AVP concentration increased and fluid-deprived sheep displayed a natriuresis and then a rehydration anti-natriuresis. Sheep did not drink the 10% ethanol solution avidly upon fluid restoration, preferring to drink steadily over the following 24 h; there was an associated increase in blood alcohol concentration (BAC). PRC, ANG II and ALDO all increased throughout the fluid restoration period, whereas plasma AVP and ANP gradually fell. In a separate experiment when water was also supplied to the sheep, they preferred water to 10% ethanol; however, alcohol intake was not eliminated. Overall, this degree of chronic consumption of 10% ethanol solution did not appear to adversely affect physiological mechanisms concerned with body fluid homeostasis after fluid deprivation conditions.

Omega-3 polyunsaturated fatty acid supplementation reduces hypertension in TGR(mRen-2)27 rats.

To establish the effect of dietary omega-3 PUFA on angiotensin II (ANG II)-mediated hypertension, male TGR (mRen-2)27 (Ren-2) rats (animals with high ANG II activity) were maintained on a diet either deficient or sufficient in omega-3 PUFA from conception. Half the animals on each diet were treated with the angiotensin-converting enzyme inhibitor, perindopril, from birth. Ren-2 rats fed the omega-3 PUFA deficient diet were significantly more hypertensive than those fed the omega-3 PUFA sufficient diet. Perindopril reduced the blood pressure of both omega-3 PUFA-deficient and omega-3 PUFA-sufficient diet-fed Ren-2 rats. Body weight, body fat and plasma leptin were reduced by perindopril treatment but not affected by omega-3 PUFA supply. Given that the elevated blood pressure of the Ren-2 rat is mediated by ANG II, the data suggest that omega-3 PUFA may reduce hypertension via the renin-angiotensin system.

The role of adrenal or testicular hormones in voluntary ethanol and NaCl intake of crowded and individually housed rats.

The effect of adrenalectomy or castration on the ingestive behaviour of 10% ethanol, 0.5 M NaCl, water, and food was investigated in 2 models of increased/high ethanol consumption (1) adult male rats, previously individually housed with low ethanol intake, moved crowded housing and (2) individually housed adult male rats with high ethanol intake in the absence of any known aetiology. In study 1, rats that had been previously individually housed were paired with an animal in a small cage with ad libitum access to 10% ethanol intake, 0.5 M NaCl, water, and food at all times. Rats significantly increased 10% ethanol intake after they were pair-housed. The pairs were either adrenalectomized, castrated or sham operated. Neither adrenalectomy nor castration resulted in a significant change in 10% ethanol intake. 0.5 M NaCl intake was elevated and food intake and body weight were decreased in adrenalectomized rats. In study 2, rats that consumed large amounts of ethanol in the absence of any known aetiology remained in individual housing. Ethanol intake was decreased subsequent to either adrenalectomy or castration; adrenalectomy resulted in an increase in 0.5 M NaCl intake. These results suggest that the influence of adrenal or testicular hormones on ethanol intake is situation dependent. The increase in ethanol intake induced by placing animals in crowded housing appears to be independent of these hormones.

Failure of conjugated linoleic acid supplementation to enhance biosynthesis of docosahexaenoic acid from alpha-linolenic acid in healthy human volunteers.

A rate-limiting step in docosahexaenoic acid (DHA) formation from alpha-linolenic acid (ALA) involves peroxisomal oxidation of 24:6n-3 to DHA. The aim of the study was to determine whether conjugated linoleic acid (CLA) would enhance conversion of ALA to DHA in humans on an ALA-supplemented diet. The subjects (n=8 per group) received daily supplementation of ALA (11g) and either CLA (3.2g) or placebo for 8 weeks. At baseline, 4 and 8 weeks, blood was collected for plasma fatty acid analysis and a number of physiological measures were examined. The ALA-supplemented diet increased plasma levels of ALA and eicosapentaenoic acid (EPA). The addition of CLA to the ALA diet resulted in increased plasma levels of CLA, as well as ALA and EPA. Plasma level of DHA was not increased with either the ALA alone or ALA plus CLA supplementation. The results demonstrated that CLA was not effective in enhancing DHA levels in plasma in healthy volunteers.