Adrenalectomy improves glycemic responses in congenic obese LA/Ntul//-cp RATS

To determine the effects of adrenalectomy on typical insulin-mediated glycemic responses in male obese rats, groups (n=6 -12 rats/phenotype) of normally reared congenic lean and obese animals were fed a Purina chow diet from 6 to 9 weeks of age, and the Chow diet plus a highly palatable cafeteria diet from 9 to 12 weeks of age. The congenic LA/Ntul//-cp rat strain is noted for its longevity and early expression of the obese trait but remains non-diabetic throughout much if not all of its normal lifespan. Subgroups of obese animals were subjected to bilateral adrenalectomy (ADX) at 6 weeks of age to remove glucocorticoid contributions to glycemic parameters. Measures of weight gain (WG )and of glucose tolerance (OGT) were obtained in the three treatment groups at 6, 9 and 12 weeks of age. WG on ADX-obese rats was similar to that of their lean littermates at 6 and 9 weeks of age on the chow diet but increased to twice that observed in their lean littermates from 9 to 12 weeks of age. OGT responses after 30 to 60 minutes and the area under the OGT curve were impaired but not diabetic in obese animals at all ages compared to lean littermates and returned toward those of normally lean rats after ADX. The Insulin to glucose ratio (I:G) was also consistent with insulin resistance in obese but not in ADX-obese or lean rats at 12 weeks of age. In conclusion, ADX resulted in normalization of OGT and glycemic parameters in the obese phenotype at 9 and 12 weeks of age. These results are consistent with normalization of typical insulin-mediated components of glycemic parameters and glucose uptake in peripheral tissues following adrenalectomy of congenic obese rats. The results further suggest that the counterregulatory effects of insulin and glucocorticoid hormones may be contributory to the impaired glycemic responses in the obese phenotype of the LA/N//-cp (corpulent) rat and are consistent with a receptor-mediated element in the development of insulin resistance and glucose uptake in peripheral tissues commonly associated with the early development of obesity in this strain.

Effect of adrenalectomy and glycemic status on caloric efficiency and adiposity in the congenic LA/Ntul//-cp (corpulent) rat

Obesity develops in the obese phenotype of the congenic LA/Ntul//-cp (corpulent) rat strain by 6 weeks of age.1 To gain insight into the contributors to the expression of obesity in the obese phenotype of this strain, groups [n=12-20 rats/phenotype] of congenic male lean and obese LA/Ntul//-cp (corpulent) rats were fed an ad libitum standardized Purina chow diet (CHOW) from 6 to 12 weeks or age, and subgroups (n=6 rats / subgroup) were overfed with a highly palatable cafeteria diet (CAFÉ) from 9 to 12 weeks of age (WOA). A subgroup of obese rats (n=6) were subjected to bilateral adrenalectomy (ADX) at 6 WOA and followed the same dietary regimen and treatment schedule. BW of lean and obese animals were similar at 6 WOA and increased by 88% in lean phenotype and 281% in obese phenotype during the 6 weeks study, while in ADX obese rats, BW were similar at 6 and 9 WOA but BW increased to 2.5-fold above starting weights and 1.8-fold above 9-week weights between 9 and 12 WOA. The CAFE supplement was without significant effect on final body weights in the lean phenotypes, but was associated with significantly greater body weights at ages 9 and 12 WOA in the obese phenotype (p=<0.05) and in the obese-ADX at 12 WOA. CE (kcal/gram gain of BW per day) remained relatively constant in lean and obese-ADX rats throughout the study, but CE was more efficient in the obese phenotype at all ages studied and was more efficient with the CAFE supplement feeding regimen. Fasting I:G ratios at 12 weeks of age were 4.2-fold greater in obese than lean and were partially normalized in obese-ADX to 1.7-fold increase at 12 WOA. Relative adiposity of obese rats was 3.8-fold greater in obese than lean phenotype, with the greatest increase in the SQ depot. Resting VO2 (RMR) was lower in obese than lean rats at each age studied and was increased by ADX. Thermogenic interscapular brown adipose tissue (IBAT) mass was greater in obese and obese-ADX than lean rats. The results of this study indicate that CE is associated with the predisposition for the expression and development of adiposity in the obese phenotype of this strain and is associated with an increased I:G ratio and IBAT mass that is consistent with insulin resistance and an impaired capacity for energy expenditure and became normalized on the Chow but not the CAFE diet following ADX. These observations implicate likely multiple metabolic factors that contribute to a greater efficiency of energy storage, utilization and or energy conservation in the obese than in the lean phenotype of this strain and which is partially corrected in the obese phenotype by ADX. The metabolic impact of added caloric intake was associated with an additive impact on the CE of weight gain and adiposity in the obese phenotype of this congenic rodent strain and was partially corrected via ADX

163Lunch establishments are associated to metabolic phenotypes in Brazilian adults: CUME project

Background Studies have shown the relationship between food environment and obesity, but few explore metabolic phenotypes as outcomes. Methods We studied 4,311 adults (2,916 women, 1,395 men, with a mean age of 35.9 ± 9.4 y) from the Cohort of Universities in Minas Gerais, Brazil. Participants were classified as obese (BMI ≥ 30 kg/m²) or non-obese. Additionally, metabolic phenotypes were classified as healthy and unhealthy (≥ 1 conditions) based on the prevalence of hypertension, diabetes mellitus, hypercholesterolemia and hypertriglyceridemia. We also evaluated the type of food establishment where participants usually had lunch. Multinomial logistic regression analyzes were used to assess the relationship between lunch establishments and metabolic phenotypes, using the Metabolically Healthy Non-Obesity as reference category. Results The Metabolically Healthy Obese (MHO) phenotype represented 4.6% and 40.5% of the total sample and obese population, respectively. We found no associations between having lunch at home, in university restaurants or à la carte restaurants with metabolic phenotypes. Having lunch at large fast-food chains increased 1.88 (95% 1.22 - 2.90) times the chance of healthy obese phenotype and 1.56 (95% 1.03 - 2.37) times the chance of unhealthy obese phenotype. Conclusions The food habit of having lunch in unhealthy food establishments was associated with obesity, regardless of the classification of the metabolic phenotype. Key messages The habit of having lunch in fast food restaurants is associated with obesity. Metabolically healthy obesity can be a transient state up to the unhealthy phenotype. This population must also be the target of nutritional interventions.

Leptin Receptor Compound Heterozygosity in Humans and Animal Models

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones. Recently, we discovered a spontaneous compound heterozygous mutation within the leptin receptor, resulting in a considerably more obese phenotype than described for the homozygous leptin receptor deficient mice. Accordingly, we focus on compound heterozygous mutations of the leptin receptor and their effects on health, as well as possible therapy options in human and animal models in this review.

IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington's disease mouse model

Background: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, and underlying mechanisms are not fully known. As the IKKβ/NF-kB pathway is an essential regulator of metabolism, we investigated the involvement of IKKβ, the upstream activator of NF-kB in hypothalamus-specific HD metabolic changes. Methods: Using viral vectors, we expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) fragments in the hypothalamus of mice without IKKβ in the CNS (IKKβ-/-) and control mice (IKKβ+/+). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. Results: Hypothalamic expression of mHTT led to an obese phenotype only in female mice. CNS-specific inactivation of IKKβ prohibited weight gain in females, which was independent of neuroprotection and microglial activation. Conclusions: The expression of mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKKβ pathway attenuates the obese phenotype.