It is generally assumed that white adipocytes arise from resident adipose tissue mesenchymal progenitor cells. We challenge this paradigm by defining a hematopoietic origin for both the de novo development of a subset of white adipocytes in adults and a previously uncharacterized adipose tissue resident mesenchymal progenitor population. Lineage and cytogenetic analysis revealed that bone marrow progenitor (BMP)-derived adipocytes and adipocyte progenitors arise from hematopoietic cells via the myeloid lineage in the absence of cell fusion. Global gene expression analysis indicated that the BMP-derived fat cells are bona fide adipocytes but differ from conventional white or brown adipocytes in decreased expression of genes involved in mitochondrial biogenesis and lipid oxidation, and increased inflammatory gene expression. The BMP-derived adipocytes accumulate with age, occur in higher numbers in visceral than in subcutaneous fat, and in female versus male mice. BMP-derived adipocytes may, therefore, account in part for adipose depot heterogeneity and detrimental changes in adipose metabolism and inflammation with aging and adiposity.

Maternal obesity is associated with increased risk for offspring obesity and non-alcoholic fatty liver disease (NAFLD), but the causal drivers of this association are unclear. Early colonization of the infant gut by microbes plays a critical role in establishing immunity and metabolic function. Here, we compare germ-free mice colonized with stool microbes (MB) from 2-week-old infants born to obese (Inf-ObMB) or normal-weight (Inf-NWMB) mothers. Inf-ObMB-colonized mice demonstrate increased hepatic gene expression for endoplasmic reticulum stress and innate immunity together with histological signs of periportal inflammation, a histological pattern more commonly reported in pediatric cases of NAFLD. Inf-ObMB mice show increased intestinal permeability, reduced macrophage phagocytosis, and dampened cytokine production suggestive of impaired macrophage function. Furthermore, exposure to a Western-style diet in Inf-ObMB mice promotes excess weight gain and accelerates NAFLD. Overall, these results provide functional evidence supporting a causative role of maternal obesity-associated infant dysbiosis in childhood obesity and NAFLD.

Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, inflammation, and oxidative stress. To investigate whether the transcription factor CCAAT/Enhancer binding protein (C/ EBP␤) is involved in the development of NASH, C57BL/6J wild-type (WT) or C/EBP␤ knockout (C/EBP␤؊/؊) mice were fed either a methionine and choline deficient (MCD) diet or standard chow. These WT mice fed a MCD diet for 4 weeks showed a 2-to 3-fold increase in liver C/EBP␤ messenger RNA and protein, along with increased expression of lipogenic genes peroxisome proliferators-activated receptor ␥ and Fas. WT mice also showed increased levels of the endoplasmic reticulum stress pathway proteins phosphorylated eukaryotic translation initiation factor ␣, phosphorylated pancreatic endoplasmic reticulum kinase, and C/EBP homologous protein, along with inflammatory markers phosphorylated nuclear factor B and phosphorylated C-jun N-terminal kinase compared to chow-fed controls. Cytochrome P450 2E1 protein and acetyl coA oxidase messenger RNA involved in hepatic lipid peroxidation were also markedly increased in WT MCD diet-fed group. In contrast, C/EBP␤؊/؊ mice fed a MCD diet showed a 60% reduction in hepatic triglyceride accumulation and decreased liver injury as evidenced by reduced serum alanine aminotransferase and aspartate aminotransferase levels, and by H&E staining. Immunoblots and real-time qPCR data revealed a significant reduction in expression of stress related proteins and lipogenic genes in MCD diet-fed C/EBP␤؊/؊ mice. Furthermore, circulating TNF␣ and expression of acute phase response proteins CRP and SAP were significantly lower in C/EBP␤؊/؊ mice compared to WT mice. Conversely, C/EBP␤ over-expression in livers of WT mice increased steatosis, nuclear factor-B, and endoplasmic reticulum stress, similar to MCD dietfed mice. Conclusion: Taken together, these data suggest a previously unappreciated molecular link between C/EBP␤, hepatic steatosis and inflammation and suggest that increased C/EBP␤ expression may be an important factor underlying events leading to NASH. (HEPATOLOGY 2007;45:1108-1117

OBJECTIVEDiet therapy in gestational diabetes mellitus (GDM) has focused on carbohydrate restriction but is poorly substantiated. In this pilot randomized clinical trial, we challenged the conventional low-carbohydrate/higher-fat (LC/CONV) diet, hypothesizing that a higher–complex carbohydrate/lower-fat (CHOICE) diet would improve maternal insulin resistance (IR), adipose tissue (AT) lipolysis, and infant adiposity.RESEARCH DESIGN AND METHODSAt 31 weeks, 12 diet-controlled overweight/obese women with GDM were randomized to an isocaloric LC/CONV (40% carbohydrate/45% fat/15% protein; n = 6) or CHOICE (60%/25%/15%; n = 6) diet. All meals were provided. AT was biopsied at 37 weeks.RESULTSAfter ∼7 weeks, fasting glucose (P = 0.03) and free fatty acids (P = 0.06) decreased on CHOICE, whereas fasting glucose increased on LC/CONV (P = 0.03). Insulin suppression of AT lipolysis was improved on CHOICE versus LC/CONV (56 vs. 31%, P = 0.005), consistent with improved IR. AT expression of multiple proinflammatory genes was lower on CHOICE (P < 0.01). Infant adiposity trended lower with CHOICE (10.1 ± 1.4 vs. 12.6 ± 2%, respectively).CONCLUSIONSA CHOICE diet may improve maternal IR and infant adiposity, challenging recommendations for a LC/CONV diet.

CCAAT/enhancer-binding protein ␤ (C/EBP␤) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBP␤ in hepatic lipogenesis remains undefined. Here we show that C/EBP␤ inactivation in Lepr db/db mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBP␤ ؊/؊ x Lepr db/db mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBP␤ deletion in Lepr db/db mice down-regulated peroxisome proliferator-activated receptor ␥2 (PPAR␥2) and stearoyl-CoA desaturase-1 and up-regulated PPAR␣ independent of SREBP1c. Conversely, C/EBP␤ overexpression in wild-type mice increased PPAR␥2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBP␤ or C/EBP␤ RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPAR␥2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBP␤ expression in hepatocytes, whereas fatty acids up-regulate C/EBP␤ expression. These data provide novel evidence linking C/EBP␤ expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.Obesity is the most common nutritional disorder in Western societies. Today in the United States, more than 60% of people are either overweight (body mass index (BMI) Ͼ 25) or obese (BMI Ͼ 30) (1). Obesity is frequently associated with type II diabetes, hypertension, and hyperlipidemia, all known risk factors for cardiovascular disease (2). Obesity is also a major risk factor for non-alcoholic fatty liver disease, one of the most common emerging liver diseases in Western countries coinciding with the worldwide obesity epidemic (3, 4). The underlying transcriptional events that contribute to obesity and its associated disorders are not well understood. Some of the genes that regulate body weight have been identified as well as additional neuropeptides, hormones, and nutritional factors that play a role in body weight regulation, particularly through the ␤-adrenergic system (5, 6). Discovery of the hormone leptin and its receptors, which suppress appetite and reduce fat mass, has dramatically increased our understanding of the regulation of energy balance (7,8). More recently, the study of specific transcription factor genes and their metabolism has provided powerful new tools for understanding the integrated mechanisms underlying obesity and diabetes (9 -11). This is most elegantly illustrated using tissue-specific gene knockouts and overexpression models to elucidate the mechanism of action of the PPAR 5 family of nuclear hormone receptors (12). The CCAAT/enhancer-binding protein (C/EBP) family includes five nuclear transcription factors, C/EBP ␣, ␤, ␥, ␦, and ⑀, encoded by separate genes located on different chromosomes (13,14). Collectively, C/EBPs are expressed across a variety of cell types, and...