Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue i...

Brown Adipose Tissue: Function and Physiological Significance

The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution However, the presence of excess adipose tissue can be maladaptive A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system Leptin also signals nutritional status to several other physiological systems and modulates their function Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity

Leptin and the regulation of body weight in mammals

https://www.mergenmetz.nl/menn/wp-content/uploads/2012/07/Insirine-of-bewegen-artikel-in-Cell.pdf

Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human

Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible 'brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.

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Brown and beige fat: development, function and therapeutic potential

A mitochondrial protein called uncoupling protein (UCP1) plays an important role in generating heat and burning calories by creating a pathway that allows dissipation of the proton electrochemical gradient across the inner mitochondrial membrane in brown adipose tissue, without coupling to any other energy-consuming process. This pathway has been implicated in the regulation of body temperature, body composition and glucose metabolism. However, UCP1-containing brown adipose tissue is unlikely to be involved in weight regulation in adult large-size animals and humans living in a thermoneutral environment (one where an animal does not have to increase oxygen consumption or energy expenditure to lose or gain heat to maintain body temperature), as there is little brown adipose tissue present. We now report the discovery of a gene that codes for a novel uncoupling protein, designated UCP2, which has 59% amino-acid identity to UCP1, and describe properties consistent with a role in diabetes and obesity. In comparison with UCP1, UCP2 has a greater effect on mitochondrial membrane potential when expressed in yeast. Compared to UCP1, the gene is widely expressed in adult human tissues, including tissues rich in macrophages, and it is upregulated in white fat in response to fat feeding. Finally, UCP2 maps to regions of human chromosome 11 and mouse chromosome 7 that have been linked to hyperinsulinaemia and obesity. Our findings suggest that UCP2 has a unique role in energy balance, body weight regulation and thermoregulation and their responses to inflammatory stimuli.

Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia

We have previously demonstrated that the C57BL/6J (B/6J) mouse will develop severe obesity, hyperglycemia, and hyperinsulinemia if weaned onto a high-fat, high-sucrose (HH) diet. In the present study, we compared the effects of fat and sucrose separately and in combination on diabetes- and obesity-prone B/6J and diabetes- and obesity-resistant A/J mice. After 4 months, the feed efficiency ([FE] weight gained divided by calories consumed) did not differ across diets in A/J mice, but B/6J mice showed a significantly increased FE for fat. That is, B/6J mice gained more weight on high-fat diets without consuming more calories than A/J mice. The increase in FE was related to adipocyte hyperplasia in B/6J mice on high-fat diets. Fat-induced obesity in B/6J mice was unrelated to adrenal cortical activity. In the absence of fat, sucrose produced a decreased in FE in both strains. Animals fed a low-fat, high-sucrose (LH) diet were actually leaner than animals fed a high-complex-carbohydrate diet. Fat was also found to be the critical stimulus for hyperglycemia and hyperinsulinemia in B/6J mice. In the absence of fat, sucrose had no effect on plasma glucose or insulin. These data clearly show that across these two strains of mice, genetic differences in the metabolic response to fat are more important in the development of obesity and diabetes than the increased caloric content of a high-fat diet.

Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A J mice

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Role of leptin in fat regulation

Uncoupling protein 2 (UCP2) maps to a region on distal mouse chromosome 7 that has been linked to the phenotypes of obesity and type II diabetes. We recently reported that UCP2 expression is increased by high fat feeding in adipose tissue of the A/J strain of mice, which is resistant to the development of dietary obesity. More recently, a third UCP (UCP3) was identified, which is expressed largely in skeletal muscle and brown adipose tissue. The UCP2 and UCP3 genes are located adjacent to one another on mouse chromosome 7. Thus, the roles of these UCPs in both metabolic efficiency and the linkage to obesity and diabetes syndromes is unclear. For this reason, we examined the expression of UCP2 and UCP3 in white adipose tissue and interscapular brown adipose tissue and in gastrocnemius/soleus muscle preparations from the obesity-resistant A/J and C57BL/KsJ (KsJ) strains and the obesity-prone C57BL/6J (B6) mouse strain. In both KsJ and A/J mice, UCP2 expression in white fat was increased ≈2-fold in response to 2 weeks of a high fat diet, but there was no effect of diet on UCP2 levels in B6 mice. In skeletal muscle and in brown fat, neither UCP2 nor UCP3 expression was affected by diet in A/J, B6, or KsJ mice. However, in brown fat, we observed a 2–3-fold increase in the expression of UCP1 in response to dietary fat challenge, which may be related to diet-induced elevations in plasma leptin levels. Together, these results indicate that the consumption of a high fat diet selectively regulates UCP2 expression in white fat and UCP1 expression in brown fat and that resistance to obesity is correlated with this early, selective induction of UCP1 and UCP2 and is not associated with changes in expression of UCP3.

https://www.pnas.org/content/pnas/95/7/4061.full.pdf

Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice

Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.

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Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator.

Fat intake has long been associated with the development of obesity. The studies described herein show that fat adversely affects adipocyte adrenergic receptor (AR) expression and function. As beta 3AR agonists have been shown to acutely reduce adipose tissue mass and improve thermogenesis in genetically obese rodents, we examined whether chronic supplementation of a high fat diet with a highly selective beta 3AR agonist, CL316,243 could prevent diet-induced obesity, and whether the effect could be sustained over prolonged treatment. C57BL/6J and A/J mice were weaned onto one of three diets: low fat (10.5% calories from fat), high fat (58% calories from fat), or high fat supplemented with 0.001% CL316,243. B/6J mice gained more weight on the high fat diet than A/J mice (at 16 weeks: B/6J, 36.6 +/- 1.4 g; A/J, 32.9 +/- 0.8 g; P 0.05; n = 10). CL316,243 prevented the development of diet-induced obesity in A/J animals, but not in B/6J animals. A/J mice weighed 26.0 +/- 0.5 g at 16 weeks, whereas B/6J animals on the same diet weighed 34.1 +/- 0.8 g (P < 0.00001; n = 10), but food intake was not different between the strains throughout the study. beta-Adrenergic stimulation of adenylyl cyclase in obese B/6J mice was decreased by more than 75% in white adipose tissue and by more than 90% in brown adipose tissue (BAT). In contrast, in fat-fed A/J mice, beta-agonist-stimulated adenylyl cyclase was decreased in white adipose tissue by about 10%, whereas the activity in interscapular BAT was decreased by 50%, indicating significant retention of beta AR-stimulated activity in A/J mice compared to B/6J mice. High fat feeding was associated with decreased expression of beta 3AR and beta 1AR in white adipose tissue of both strains. However, chronic CL316,243 treatment prevented both the obesity and the decline in beta 3AR and beta 1AR messenger RNA levels in all adipose depots from A/J mice, but not B/6J mice. As CL316,243-treated A/J mice, but not B/6J mice, also showed marked uncoupling protein expression in white adipose depots, the ability of chronic CL316,243 treatment to prevent diet-induced obesity is dependent upon the elaboration of functional BAT in these regions.

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Ann Petro

Papers

Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A J mice

Role of leptin in fat regulation

Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice

Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator.

Strain-specific response to beta 3-adrenergic receptor agonist treatment of diet-induced obesity in mice.