Female mice lacking p47^phoxhave altered adipose tissue gene expression and are protected against high fat-induced obesity

Abstract

Female mice lacking p47 phox have altered adipose tissue gene expression and are protected against high fat-induced obesity. Physiol Genomics 45: 351-366, 2013. First published March 12, 2013 doi:10.1152/physiolgenomics.00148.2012.-The current study was designed to determine if the NADPH-oxidase NOX2 plays a role in development of obesity after high fat feeding. Wild-type (WT) mice and mice lacking the essential cytosolic NOX2 system component p47 phox (P47KO mice) were fed AIN-93G diets or high-fat diets (HFD) containing 45% fat and 0.5% cholesterol for 13 wk from weaning. Fat mass was increased to a similar degree by HFD in males of both genotypes (P Ͻ 0.05). However, female P47KO-HFD mice had no increase in adiposity or adipocyte size relative to female WT-HFD mice. Resistance to HFD-driven obesity in P47KO females was associated with increased expression of hepatic TFAM and UCP-2 mRNA, markers of mitochondrial number and uncoupling, and increased expression of hepatic mitochondrial respiratory complexes and whole body energy expenditure in response to HFD. Microarray analysis revealed significantly lower expression of mRNA encoding genes linked to energy metabolism, adipocyte differentiation (PPAR␥), and fatty acid uptake (CD36, lipoprotein lipase), in fat pads from female P47KO-HFD mice compared with WT-HFD females. Moreover, differentiation of preadipocytes ex vivo was suppressed more by 17␤-estradiol in cells from P47KO compared with cells from WT females in conjunction with overexpression of mRNA for Pref-1 (P Ͻ 0.05). HFD mice of both sexes were resistant to the development of hyperglycemia and hepatic steatosis (P Ͻ 0.05) and had reduced serum triglycerides, leptin, and adiponectin relative to WT-HFD mice (P Ͻ 0.05). These data suggest that NOX2 is an important regulator of metabolic homeostasis and diet-induced obesity.

Redox modulation of adipocyte differentiation: hypothesis of “Redox Chain” and novel insights into intervention of adipogenesis and obesity

“…lipid peroxidation [176].In particular, CoQ is deficient in WAT of ob/ob mice. In rodents as well as in humans, CoQ content is strongly and negatively correlated with subcutaneous adipose tissue and obesity indexes [315].…”

“…Butylhydroxyanisole inhibits lipid accumulation and adipocyte differentiation in 3T3-F442A in a concentration-dependent manner [176].…”

“…The decreased CAT activity resulting from its promoter mutation is positively associated with childhood obesity and obesity biomarkers such as weight, BMI, and aP2, along with a tendency toward significance with insulin resistance biomarkers [236]. However, in inguinal WAT in obese Zucker rats, CAT activities were found to be increased significantly [176]. Similarly, CAT expression and activity are greatly elevated along with the progression of 3T3-L1 adipocyte differentiation [234].…”

“…As a component of the NOX, p47 phox is shown to be positively related with adipocyte differentiation. Mice lacking p47 phox are protected against HF diet-induced increase of adiposity, adipocyte size and hepatic steatosis [176] and alcohol-induced hepatic steatosis [177].Whether other NOX isoforms are involved in adipogenesis is currently unclear.…”

Fatty acid metabolism, energy expenditure and insulin resistance in muscle

“…Despite this, it is not uncommon to read about studies in whole animal systems (particularly genetically modified mice) where differences in fat mass are often mechanistically related to changes in the mRNA levels of FA metabolism genes in a variety of tissues without appropriate consideration of the contribution of these tissues to whole-body energy expenditure (AbuElheiga et al 2001, 2003, Lee et al 2009, Hu et al 2012, Ronis et al 2013. In the context of investigations of energy balance in lean and obese mice, there are excellent recent reviews pointing out potential problems with assessing differences in food intake and energy expenditure using indirect calorimetry systems and extrapolating any differences to explain gain or loss of fat mass (Butler & Kozak 2010, Tschop et al 2012.…”