Michelle T. Foster

Central angiotensin II has catabolic action at white and brown adipose tissue

Considerable evidence implicates the renin-angiotensin system (RAS) in the regulation of energy balance. To evaluate the role of the RAS in the central nervous system regulation of energy balance, we used osmotic minipumps to chronically administer angiotensin II (Ang II; icv; 0.7 ng/min for 24 days) to adult male Long-Evans rats, resulting in reduced food intake, body weight gain, and adiposity. The decrease in body weight and adiposity occurred relative to both ad libitum- and pair-fed controls, implying that reduced food intake in and of itself does not underlie all of these effects. Consistent with this, rats administered Ang II had increased whole body heat production and oxygen consumption. Additionally, chronic icv Ang II increased uncoupling protein-1 and β(3)-adrenergic receptor expression in brown adipose tissue and β3-adrenergic receptor expression in white adipose tissue, which is suggestive of enhanced sympathetic activation and thermogenesis. Chronic icv Ang II also increased hypothalamic agouti-related peptide and decreased hypothalamic proopiomelanocortin expression, consistent with a state of energy deficit. Moreover, chronic icv Ang II increased the anorectic corticotrophin- and thyroid-releasing hormones within the hypothalamus. These results suggest that Ang II acts in the brain to promote negative energy balance and that contributing mechanisms include an alteration in the hypothalamic circuits regulating energy balance, a decrease in food intake, an increase in energy expenditure, and an increase in sympathetic activation of brown and white adipose tissue.

Diet-induced Obese Mice Are Leptin Insufficient After Weight Reduction

Behavioral therapies aimed at reducing excess body fat result in limited fat loss after dieting. To understand the causes for maintenance of adiposity, high‐fat (HF) diet–induced obese (DIO) mice were switched to a low‐fat chow diet, and the effects of chow on histological and molecular alterations of adipose tissue and metabolic parameters were examined. DIO mice reduced and stabilized their body weights after being switched to chow (HF‐chow), but retained a greater amount of adiposity than chow‐fed mice. Reduction in adipocyte volume, not number, caused a decrease in fat mass. HF‐chow mice showed normalized circulating insulin and leptin levels, improved glucose tolerance, and reduced inflammatory status in white adipose tissue (WAT). Circulating leptin levels corrected for fat mass were lower in HF‐chow mice. Leptin administration was used to test whether reduced leptin level of HF‐chow mice inhibited further fat loss. Leptin treatment led to an additional reduction in adiposity. Finally, HF‐HF mice had lower mRNA levels of β3 adrenergic receptor (β3‐AR) in epididymal WAT (EWAT) compared to chow‐fed mice, and diet change led to an increase in the WAT β3‐AR mRNA levels that were similar to the levels of chow‐fed mice, suggesting an elevation in sympathetic activation of WAT during diet switch relative to HF‐HF mice leading to the reduced leptin level and proinflammatory cytokine content. In summary, HF‐chow mice were resistant to further fat loss due to leptin insufficiency. Diet alteration from HF to low fat improved metabolic state of DIO mice, although their adiposity was defended at a higher level.

Subcutaneous adipose tissue transplantation in diet‐induced obese mice attenuates metabolic dysregulation while removal exacerbates it

Adipose tissue distribution is an important determinant of obesity‐related comorbidities. It is well established that central obesity (visceral adipose tissue accumulation) is a risk factor for many adverse health consequences such as dyslipidemia, insulin resistance, and type‐2‐diabetes. We hypothesize that the metabolic dysregulation that occurs following high fat diet‐induced increases in adiposity are due to alterations in visceral adipose tissue function which influence lipid flux to the liver via the portal vein. This metabolic pathology is not exclusively due to increases in visceral adipose tissue mass but also driven by intrinsic characteristics of this particular depot. In Experiment 1, high fat diet (HFD)‐induced obese control (abdominal incision, but no fat manipulation) or autologous (excision and subsequent relocation of adipose tissue) subcutaneous tissue transplantation to the visceral cavity. In Experiment 2, mice received control surgery, subcutaneous fat removal, or heterotransplantation (tissue from obese donor) to the visceral cavity. Body composition analysis and glucose tolerance tests were performed 4 weeks postsurgery. Adipose mass and portal adipokines, cytokines, lipids, and insulin were measured from samples collected at 5 weeks postsurgery. Auto‐ and heterotransplantation in obese mice improved glucose tolerance, decreased systemic insulin concentration, and reduced portal lipids and hepatic triglycerides compared with HFD controls. Heterotransplantation of subcutaneous adipose tissue to the visceral cavity in obese mice restored hepatic insulin sensitivity and reduced insulin and leptin concentrations to chow control levels. Fat removal, however, as an independent procedure exacerbated obesity‐induced increases in leptin and insulin concentrations. Overall subcutaneous adipose tissue protects against aspects of metabolic dysregulation in obese mice. Transplantation‐induced improvements do not occur via enhanced storage of lipid in adipose tissue, however, altered hepatic lipid regulation may play a contributory role.

Metabolic alterations following visceral fat removal and expansion: Beyond anatomic location.

Increased visceral adiposity is a risk factor for metabolic disorders such as dyslipidemia, hypertension, insulin resistance and type 2 diabetes, whereas peripheral (subcutaneous) obesity is not. Though the specific mechanisms which contribute to these adipose depot differences are unknown, visceral fat accumulation is proposed to result in metabolic dysregulation because of increased effluent, e.g., fatty acids and/or adipokines/cytokines, to the liver via the hepatic portal vein. Pathological significance of visceral fat accumulation is also attributed to adipose depot/adipocyte-specific characteristics, specifically differences in structural, physiologic and metabolic characteristics compared with subcutaneous fat. Fat manipulations, such as removal or transplantation, have been utilized to identify location dependent or independent factors that play a role in metabolic dysregulation. Obesity-induced alterations in adipose tissue function/intrinsic characteristics, but not mass, appear to be responsible for obesity-induced metabolic dysregulation, thus “quality” is more important than “quantity.” This review summarizes the implications of obesity-induced metabolic dysfunction as it relates to anatomic site and inherent adipocyte characteristics.

Transplantation or removal of intra-abdominal adipose tissue prevents age-induced glucose insensitivity.

Increases in intra-abdominal fat, a common feature associated with aging, is an established risk factor for insulin resistance, diabetes and the metabolic syndrome. To examine the direct contribution of intra-abdominal fat in the pathophysiology of insulin resistance we altered fat volume via removal or transplantation in a naturally occurring age-induced moderate model of obesity and insulin resistance. This was accomplished by bilateral removal of epididymal white adipose tissue (Lipx) or transplantation of donor fat into the intra-abdominal side of the peritoneal cavity of 28-week old rats. Control animals received sham surgery. Glucose tolerance was evaluated at baseline and 4 and 8weeks post-surgery in all groups, and fasting insulin and leptin were additionally measured in 28-week old rats. In addition, fasted and fed triglyceride, cholesterol and fatty acid concentrations were measured. Before surgery 28-week old rats weighed more and were glucose intolerant compared with 8-week old controls. Both Lipx and transplantation significantly prevented age-induced decreases in glucose tolerance, with Lipx causing improvement at 4weeks which declined by 8weeks; and with a significant transplantation improvement at 8weeks only. Lipx significantly increased insulin secretion 15min after a bolus injection of 0.75mg/kg dextrose at 4 and 8weeks compared with controls, while transplantation caused a significant ( approximately 220%) increase in fasted leptin level at 4weeks only. Taken together, these data suggest that surgical removal or addition of intra-abdominal fat prevents age-induced insulin resistance by different mechanisms and is a suitable model to investigate naturally occurring obesity.

Removal of intra-abdominal visceral adipose tissue improves glucose tolerance in rats: Role of hepatic triglyceride storage ☆

Epidemiological studies have demonstrated a strong link between increased visceral fat and metabolic syndrome. In rodents, removal of intra-abdominal but non-visceral fat improves insulin sensitivity and glucose homeostasis, though previous studies make an imprecise comparison to human physiology because actual visceral fat was not removed. We hypothesize that nutrient release from visceral adipose tissue may have greater consequences on metabolic regulation than nutrient release from non-visceral adipose depots since the latter drains into systemic but not portal circulation. To assess this we surgically decreased visceral white adipose tissue (~0.5 g VWATx) and compared the effects to removal of non-visceral epididymal fat (~4 g; EWATx), combination removal of visceral and non-visceral fat (~4.5 g; EWATx/VWATx) and sham-operated controls, in chow-fed rats. At 8 weeks after surgery, only the groups with visceral fat removed had a significantly improved glucose tolerance, although 8 times more fat was removed in EWATx compared with VWATx. This suggests that mechanisms controlling glucose metabolism are relatively more sensitive to reductions in visceral adipose tissue mass. Groups with visceral fat removed also had significantly decreased hepatic lipoprotein lipase (LPL) and triglyceride content compared with controls, while carnitine palmitoyltransferase (CPT-1A) was decreased in all fat-removal groups. In a preliminary experiment, we assessed the opposite hypothesis; i.e., we transplanted excess visceral fat from a donor rat to the visceral cavity (omentum and mesentery), which drains into the hepatic portal vein, of a recipient rat but observed no major metabolic effect. Overall, our results indicate surgical removal of intra-abdominal fat improves glucose tolerance through mechanism that may be mediated by reductions in liver triglyceride.

Ovariectomy results in differential shifts in gut microbiota in low versus high aerobic capacity rats

The increased risk for cardiometabolic disease with the onset of menopause is widely studied and likely precipitated by the decline in endogenous estradiol (E2), yet the precise mechanisms are unknown. The gut microbiome is involved in estrogen metabolism and has been linked to metabolic disease, suggesting its potential involvement in the postmenopausal phenotype. Furthermore, menopause‐associated risk factors, as well as gut ecology, are altered with exercise. Therefore, we studied microbial changes in an ovariectomized (OVX vs. Sham) rat model of high (HCR) and low (LCR) intrinsic aerobic capacity (n = 8–10/group) in relation to changes in body weight/composition, glucose tolerance, and liver triglycerides (TG). Nine weeks after OVX, HCR rats were moderately protected against regional adipose tissue gain and liver TG accumulation (P < 0.05 for both). Microbial diversity and number of the Bacteroidetes phylum were significantly increased in LCR with OVX, but unchanged in HCR OVX relative to Sham. Plasma short‐chain fatty acids (SCFA), produced by bacteria in the gut and recognized as metabolic signaling molecules, were significantly greater in HCR Sham relative to LCR Sham rats (P = 0.05) and were decreased with OVX in both groups. These results suggest that increased aerobic capacity may be protective against menopause‐associated cardiometabolic risk and that gut ecology, and production of signaling molecules such as SCFA, may contribute to the mediation.

Fuzhuan tea consumption imparts hepatoprotective effects and alters intestinal microbiota in high saturated fat diet-fed rats.

SCOPE Nonalcoholic fatty liver disease is an obesity-related disorder characterized by lipid infiltration of the liver. Management is limited to lifestyle modifications, highlighting the need for alternative therapeutic options. The objective of this study was to examine if fermented Fuzhuan tea prevents metabolic impairments associated with development of hepatic steatosis. METHODS AND RESULTS Rats consumed control (CON) or high saturated fat (SAT) diets with or without Fuzhuan tea for 8 weeks. Outcomes included enzymatic and gene expression measures of metabolic dysregulation in liver and adipose tissue. Pyrosequencing was used to assess intestinal microbiota adaptations. Fuzhuan tea prevented diet-induced inflammation in the liver. Liver triglycerides of ∼18 mg/g were observed in SAT-fed animals, but remained similar to CON diet levels (∼12 mg/g) when supplemented with Fuzhuan tea. In adipose tissue, tea treatment prevented SAT-induced inflammation and reduced plasma leptin approximately twofold. Fuzhuan tea also altered intestinal function and was associated with a threefold increase in two Lactobacillus spp. CONCLUSIONS These data suggest that Fuzhuan tea protects against liver and adipose tissue stress induced by a high SAT diet and positively influences intestinal function. Further investigation of the molecular targets of Fuzhuan tea is warranted.

Subcutaneous inguinal white adipose tissue is responsive to, but dispensable for, the metabolic health benefits of exercise

Exercise training has robust effects on subcutaneous inguinal white adipose tissue (iWAT), characterized by a shift to a brown adipose tissue (BAT)-like phenotype. Consistent with this, transplantation of exercise-trained iWAT into sedentary rodents activates thermogenesis and improves glucose homeostasis, suggesting that iWAT metabolism may contribute to the beneficial effects of exercise. However, it is yet to be determined if adaptations in iWAT are necessary for the beneficial systemic effects of exercise. To test this, male C57BL/6 mice were provided access to voluntary wheel running (VWR) or remained as a cage control (SED) for 11 nights after iWAT removal via lipectomy (LIPX) or SHAM surgery. We found that SHAM and LIPX mice with access to VWR ran similar distances and had comparable reductions in body mass, increased food intake, and increased respiratory exchange ratio (RER). Further, VWR improved indexes of glucose homeostasis and insulin tolerance in both SHAM and LIPX mice. The lack of effect of LIPX in the response to VWR was not explained by compensatory increases in markers of mitochondrial biogenesis and thermogenesis in skeletal muscle, epididymal white adipose tissue, or interscapular brown adipose tissue. Together, these data demonstrate that mice with and without iWAT have comparable adaptations to VWR, suggesting that iWAT may be dispensable for the metabolic health benefits of exercise.

Understanding Recession and Self-Rated Health with the Partial Proportional Odds Model: An Analysis of 26 Countries

Introduction Self-rated health is demonstrated to vary substantially by both personal socio-economic status and national economic conditions. However, studies investigating the combined influence of individual and country level economic indicators across several countries in the context of recent global recession are limited. This paper furthers our knowledge of the effect of recession on health at both the individual and national level. Methods Using the Life in Transition II study, which provides data from 19,759 individuals across 26 European nations, we examine the relationship between self-rated health, personal economic experiences, and macro-economic change. Data analyses include, but are not limited to, the partial proportional odds model which permits the effect of predictors to vary across different levels of our dependent variable. Results Household experiences with recession, especially a loss of staple good consumption, are associated with lower self-rated health. Most individual-level experiences with recession, such as a job loss, have relatively small negative effects on perceived health; the effect of individual or household economic hardship is strongest in high income nations. Our findings also suggest that macroeconomic growth improves self-rated health in low-income nations but has no effect in high-income nations. Individuals with the greatest probability of “good” self-rated health reside in wealthy countries (