Rexford S Ahima

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (154)1372.85 Total impact

  • Kelly C. Allison, Namni Goel, Rexford S. Ahima
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    ABSTRACT: Animal studies of delayed eating have provided useful information regarding the potential relationship between nighttime eating and increased weight and metabolic dysregulation, which occur in the absence of increased locomotion or increased caloric intake. We first review recent studies detailing these relationships and possible mechanisms in rodents. We then examine human data showing that sleep restriction leads to increased energy intake and weight gain, followed by a review of the human phenotype of delayed eating, night eating syndrome, and its relation to weight and metabolism. Finally, we examine human experimental studies of delayed eating and discuss preliminary data that show slight weight gain, dysfunction in energy expenditure, and abnormalities in the circadian rhythms of appetitive, stress, and sleep hormones. Well-controlled, longer-term experimental studies in humans are warranted to test the effect of delayed eating without sleep restriction to clarify whether limiting or eliminating nighttime eating could lead to weight loss and significantly improve related disorders, such as diabetes and heart disease, over time.
    Current Obesity Reports. 03/2014; 3(1).
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    ABSTRACT: The reduction of functional β cell mass is a key feature of type 2 diabetes. Here, we studied metabolic functions and islet gene expression profiles of C57BL/6J mice with naturally occurring nicotinamide nucleotide transhydrogenase (NNT) deletion mutation, a widely used model of diet-induced obesity and diabetes. On high fat diet (HF), the mice developed obesity and hyperinsulinemia, while blood glucose levels were only mildly elevated indicating a substantial capacity to compensate for insulin resistance. The basal serum insulin levels were elevated in HF mice, but insulin secretion in response to glucose load was significantly blunted. Hyperinsulinemia in HF fed mice was associated with an increase in islet mass and size along with higher BrdU incorporation to β cells. The temporal profiles of glucose-stimulated insulin secretion (GSIS) of isolated islets were comparable in HF and normal chow fed mice. Islets isolated from HF fed mice had elevated basal oxygen consumption per islet but failed to increase oxygen consumption further in response to glucose or carbonyl cyanide-4-trifluoromethoxyphenylhydrazone (FCCP). To obtain an unbiased assessment of metabolic pathways in islets, we performed microarray analysis comparing gene expression in islets from HF to normal chow-fed mice. A few genes, for example, those genes involved in the protection against oxidative stress (hypoxia upregulated protein 1) and Pgc1α were up-regulated in HF islets. In contrast, several genes in extracellular matrix and other pathways were suppressed in HF islets. These results indicate that islets from C57BL/6J mice with NNT deletion mutation develop structural, metabolic and gene expression features consistent with compensation and decompensation in response to HF diet.
    PLoS ONE 01/2014; 9(2):e86815. · 3.73 Impact Factor
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    Hyeong Kyu Park, Rexford S Ahima
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    ABSTRACT: Obesity is characterized by excess accumulation of lipids in adipose tissue and other organs, and chronic inflammation associated with insulin resistance and an increased risk of type 2 diabetes. Obesity, type 2 diabetes, and cardiovascular diseases are major health concerns. Resistin was first discovered as an adipose-secreted hormone (adipokine) linked to obesity and insulin resistance in rodents. Adipocyte-derived resistin is increased in obese rodents and strongly related to insulin resistance. However, in contrast to rodents, resistin is expressed and secreted from macrophages in humans and is increased in inflammatory conditions. Some studies have also suggested an association between increased resistin levels and insulin resistance, diabetes and cardiovascular disease. Genetic studies have provided additional evidence for a role of resistin in insulin resistance and inflammation. Resistin appears to mediate the pathogenesis of atherosclerosis by promoting endothelial dysfunction, vascular smooth muscle cell proliferation, arterial inflammation, and formation of foam cells. Indeed, resistin is predictive of atherosclerosis and poor clinical outcomes in patients with coronary artery disease and ischemic stroke. There is also growing evidence that elevated resistin is associated with the development of heart failure. This review will focus on the biology of resistin in rodents and humans, and evidence linking resistin with type 2 diabetes, atherosclerosis, and cardiovascular disease.
    Diabetes & metabolism journal 12/2013; 37(6):404-414.
  • Rexford S Ahima, Mitchell A Lazar
    Science 08/2013; 341(6148):856-8. · 31.20 Impact Factor
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    ABSTRACT: BACKGROUND: Alcoholic liver disease (ALD) progresses from steatosis to inflammation, fibrosis, and cirrhosis. Although ALD has been associated with insulin resistance, it is unclear whether insulin resistance coincides with the development of steatosis. METHODS: We studied the temporal relationship of steatosis and glucose homeostasis in mice fed a Lieber-DeCarli liquid control or ethanol (EtOH) diet for 2, 4, or 8 weeks. We studied the effects of alcohol consumption on energy balance, body composition, and hepatic lipids. Glucose tolerance test was performed, and insulin sensitivity was evaluated with hyperinsulinemic-euglycemic clamp. RESULTS: EtOH-fed mice developed hepatic steatosis over time as compared with control-fed mice despite similar energy intake and expenditure, and gain in body weight and fat. EtOH-fed mice developed glucose intolerance as early as 2 weeks, while insulin resistance developed at 4 weeks. A hyperinsulinemic clamp study at 8 weeks revealed both hepatic and peripheral insulin resistance in EtOH-fed mice. Insulin resistance was associated with hepatic steatosis, increased ceramide levels, and Perilipin 2 expression. CONCLUSIONS: Chronic EtOH consumption leads to the development of hepatic steatosis, impaired glucose tolerance, and insulin resistance. These changes are independent of energy intake or expenditure, weight, whole body fat content, and inflammation. A better understanding of the processes linking EtOH-induced steatosis and abnormal glucose homeostasis may lead to novel therapies targeting the progression of ALD.
    Alcoholism Clinical and Experimental Research 02/2013; · 3.42 Impact Factor
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    ABSTRACT: PURPOSE: Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms. METHODS: The National Cancer Institute developed an innovative concept to establish a center grant mechanism in nutrition, energetics, and physical activity, referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the centers. RESULTS: Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes three animal studies, three cohort studies, four randomized clinical trials, one cross-sectional study, and two modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality. CONCLUSION: The NIH Science of Team Science group will evaluate the value added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk of cancer as well as cancer survivors.
    Cancer Causes and Control 02/2013; · 3.20 Impact Factor
  • Rexford S. Ahima, Mitchell A. Lazar
    Science 01/2013; 341(6148):856-858. · 31.03 Impact Factor
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    ABSTRACT: Globally, both the incidence of type 2 diabetes and the consumption of meat, in particular pork meat, have increased, concurrently. Processed meats have been associated with an increased risk for diabetes in observational studies. Therefore, it is important to understand the possible mechanisms of this association and the impact of meats from different species. The goal of this systematic review was to assess experimental human studies of the impact of pork intake compared with other protein sources on early markers for the development of diabetes, ie, insulin resistance, glucose intolerance, and the components of the metabolic syndrome. A systematic review was conducted searching PubMed and EMBASE and using the Cochrane and PRISMA guidelines. Eight studies were eligible and critically reviewed. Five studies were based on a single meal or single day exposure to pork, as compared with other sources of protein. The glucose-insulin response following the pork meals did not differ compared with beef, shrimp, or mixed sources of proteins. However, compared with eggs, ham (processed meat) led to a larger insulin response in nonobese subjects. Compared with whey, ham led to a smaller insulin response and a larger glucose response. These findings suggest possible mechanisms for the association between processed meat and the development of diabetes. Nonprocessed pork meats were not compared with eggs or whey. The three longer interventions (11 days to 6 months) did not show a significant impact of pork on the components of the metabolic syndrome, with the exception of a possible benefit on waist circumference and high-density lipoprotein cholesterol (one study each with significant limitations). Most of the findings are weak and there is a lack of solid evidence. The literature on the topic is limited and important research gaps are identified. Considering recent trends and projections for diabetes and pork intake, this is an important global public health question that requires more attention in order to provide improved evidence-based dietary recommendations.
    Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 01/2013; 6:347-357.
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. We previously showed that Perilipin 2 (Plin2), a member of lipid droplet protein family, is markedly increased in fatty liver, and its reduction in the liver of diet-induced obese mice by anti-sense oligonucleotide (ASO) decreased steatosis and enhanced insulin sensitivity. Plin2-ASO treatment markedly suppressed lipogenic gene expression. To gain a better understanding of the biological role of Plin2 in liver, we performed microarray analysis to determine genes differentially regulated by Plin2-ASO compared with a control (scrambled) oligonucleotide (Cont). Male C57BL/6J mice on a high fat diet were treated with Plin2- or Cont ASO for 4 weeks. Plin2-ASO decreased hepatic triglycerides, and this was associated with changes in expression of 1363 genes. We analyzed the data for functional clustering, and validated the expression of representative genes using real time PCR. On the high-fat diet, Plin2-ASO decreased the expression of enzymes involved in fatty acid metabolism (acsl1, lipe) and steroid metabolism (hmgcr, hsd3b5, hsd17b2), suggesting that Plin2 affects hepatic lipid metabolism at the transcriptional level. Plin2-ASO also increased the expression of genes involved in regulation of hepatocyte proliferation (afp, H19), mitosis (ccna2, incenp, sgol1), and extracellular matrix (col1a1, col3a1, mmp8). Plin2-ASO had similar effects on gene expression in chow-fed mice. Together, these results indicate that Plin2 has diverse metabolic and structural roles in the liver, and its down-regulation promotes hepatic fibrosis and proliferation.
    Physiological Genomics 09/2012; · 2.81 Impact Factor
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    ABSTRACT: Fatty liver disease is associated with obesity and type 2 diabetes, and hepatic lipid accumulation may contribute to insulin resistance. Histone deacetylase 3 (Hdac3) controls the circadian rhythm of hepatic lipogenesis. Here we show that, despite severe hepatosteatosis, mice with liver-specific depletion of Hdac3 have higher insulin sensitivity without any changes in insulin signaling or body weight compared to wild-type mice. Hdac3 depletion reroutes metabolic precursors towards lipid synthesis and storage within lipid droplets and away from hepatic glucose production. Perilipin 2, which coats lipid droplets, is markedly induced upon Hdac3 depletion and contributes to the development of both steatosis and improved tolerance to glucose. These findings suggest that the sequestration of hepatic lipids in perilipin 2–coated droplets ameliorates insulin resistance and establish Hdac3 as a pivotal epigenomic modifier that integrates signals from the circadian clock in the regulation of hepatic intermediary metabolism.
    Nature medicine 05/2012; 18(6):934-42. · 27.14 Impact Factor
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    ABSTRACT: Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.
    Science 03/2012; 335(6076):1638-43. · 31.20 Impact Factor
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    ABSTRACT: Lipid droplets in the liver are coated with the perilipin family of proteins, notably adipocyte differentiation-related protein (ADRP) and tail-interacting protein of 47 kDa (TIP47). ADRP is increased in hepatic steatosis and is associated with hyperlipidemia, insulin resistance, and glucose intolerance. We have shown that reducing ADRP in the liver via antisense oligonucleotide (ASO) treatment attenuates steatosis and improves insulin sensitivity and glucose tolerance. We hypothesized that TIP47 has similar effects on hepatic lipid and glucose metabolism. We found that TIP47 mRNA and protein levels were increased in response to a high-fat diet (HFD) in C57BL/6J mice. TIP47 ASO treatment decreased liver TIP47 mRNA and protein levels without altering ADRP levels. Low-dose TIP47 ASO (15 mg/kg) and high-dose TIP47 ASO (50 mg/kg) decreased triglyceride content in the liver by 35% and 52%, respectively. Liver histology showed a drastic reduction in hepatic steatosis following TIP47 ASO treatment. The high dose of TIP47 ASO significantly blunted hepatic triglyceride secretion, improved glucose tolerance, and increased insulin sensitivity in liver, adipose tissue, and muscle. These findings show that TIP47 affects hepatic lipid and glucose metabolism and may be a target for the treatment of nonalcoholic fatty liver and related metabolic disorders.
    AJP Regulatory Integrative and Comparative Physiology 02/2012; 302(8):R996-1003. · 3.28 Impact Factor
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    ABSTRACT: Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin- and nutrient-mediated hepatic metabolic regulation in vivo.
    Nature medicine 01/2012; 18(3):388-95. · 27.14 Impact Factor
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    Edward B Lee, Rexford S Ahima
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    ABSTRACT: The number of people who suffer from obesity and one or more of its adverse complications is rapidly increasing. It is becoming clear that diet, exercise, and other lifestyle modifications are insufficient strategies to combat this growing problem. Greater understanding of the mechanisms controlling our desire to feed and our ability to balance energy intake with energy expenditure are key to the development of pharmacological approaches for treating obesity. Although great strides have been made in our understanding of how the hypothalamus regulates feeding and energy balance, much less is known about how obesity affects the structure of the hypothalamus. The authors of two papers in this issue of the JCI have addressed this issue by examining the effects of obesity on neurons and glia in the hypothalamus. These studies reveal that obesity may be in part due to hypothalamic injury, which leads to inflammation and reduced neurogenesis. These findings support the notion that obesity is a disease that affects multiple organs, including the brain, and that disruption of normal brain function leads to abnormal regulation of peripheral metabolism.
    The Journal of clinical investigation 12/2011; 122(1):22-5. · 15.39 Impact Factor
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    ABSTRACT: Metabolic syndrome has deleterious effects on the CNS, and recent evidence suggests that obesity rates are higher at presentation in children who develop epilepsy. Adiponectin is secreted by adipose tissue and acts in the brain and peripheral organs to regulate glucose and lipid metabolism. Adiponectin deficiency predisposes toward metabolic syndrome, characterized by obesity, insulin resistance, impaired glucose tolerance, hyperlipidemia, and cardiovascular morbidity. To investigate the relationship between metabolic syndrome and seizures, wild-type C57BL/6J and adiponectin knock-out mice were fed a high-fat diet, followed by treatment with low doses of kainic acid to induce seizures. Adiponectin deficiency in mice fed a high-fat diet resulted in greater fat accumulation, impaired glucose tolerance, hyperlipidemia, increased seizure severity, and increased hippocampal pathology. In contrast, there were no adverse effects of adiponectin deficiency on metabolic phenotype or seizure activity in mice fed a normal (low-fat) chow diet. These findings demonstrate that metabolic syndrome modulates the outcome of seizures and brain injury.
    Journal of Neuroscience 10/2011; 31(40):14361-6. · 6.91 Impact Factor
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    ABSTRACT: This study explored the association between maternal obesity during pregnancy and the inflammatory markers, tumor necrosis factor-α, interleukin-6 and high sensitivity C-reactive protein (hs-CRP), and the cytokine, adiponectin, in the offspring. Weight, height, Tanner stage and biomarkers were measured in thirty-four 12-year-old children, from the Infant Growth Study, who were divided into high risk (HR) and low risk (LR) groups based on maternal pre-pregnancy body mass index (BMI). The two groups differed markedly in their hs-CRP levels, but no group difference was found for the other three biomarkers. The odds ratio (OR) of HR children having detectable hs-CRP levels was 16 times greater than that of LR children after adjusting for confounding variables, including BMI z-score, Tanner stages and gender (OR: 16; 95% CI: 2-123). These results suggest that maternal obesity during pregnancy is associated with later development of elevated hs-CRP in the offspring, even after controlling for weight.
    World Journal of Pediatrics 08/2011; 8(1):76-9. · 1.08 Impact Factor
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    ABSTRACT: IL-15 receptor α (IL-15Rα) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15Rα is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15Rα have unique phenotypes. IL-15 and IL-15Rα have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15Rα induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance and exercise capacity. IL-15Rα-knockout (IL-15Rα-KO) mice ran greater distances and had greater ambulatory activity than controls. Fast muscles displayed fatigue resistance and a slower contractile phenotype. The molecular signature of these muscles included altered markers of mitochondrial biogenesis and calcium homeostasis. Morphologically, fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater ratio of nuclei to fiber area. The alterations of physiological properties and increased resistance to fatigue in fast muscles are consistent with a shift toward a slower, more oxidative phenotype. Consistent with a conserved functional role in humans, a genetic association was found between a SNP in the IL15RA gene and endurance in athletes stratified by sport. Therefore, we propose that IL-15Rα has a role in defining the phenotype of fast skeletal muscles in vivo.
    The Journal of clinical investigation 08/2011; 121(8):3120-32. · 15.39 Impact Factor
  • Rexford S Ahima, Ahlam Sabri
    Gastroenterology 07/2011; 141(3):793-5. · 12.82 Impact Factor
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    ABSTRACT: The adipocyte-derived hormone adiponectin signals from the fat storage depot to regulate metabolism in peripheral tissues. Inversely correlated with body fat levels, adiponectin reduction in obese individuals may play a causal role in the symptoms of metabolic syndrome. Adiponectin lowers serum glucose through suppression of hepatic glucose production, an effect attributed to activation of AMPK. Here, we investigated the signaling pathways that mediate the effects of adiponectin by studying mice with inducible hepatic deletion of LKB1, an upstream regulator of AMPK. We found that loss of LKB1 in the liver partially impaired the ability of adiponectin to lower serum glucose, though other actions of the hormone were preserved, including reduction of gluconeogenic gene expression and hepatic glucose production as assessed by euglycemic hyperinsulinemic clamp. Furthermore, in primary mouse hepatocytes, the absence of LKB1, AMPK, or the transcriptional coactivator CRTC2 did not prevent adiponectin from inhibiting glucose output or reducing gluconeogenic gene expression. These results reveal that whereas some of the hormone's actions in vivo may be LKB1 dependent, substantial LKB1-, AMPK-, and CRTC2-independent signaling pathways also mediate effects of adiponectin.
    The Journal of clinical investigation 06/2011; 121(6):2518-28. · 15.39 Impact Factor

Publication Stats

14k Citations
1,372.85 Total Impact Points

Institutions

  • 2001–2014
    • University of Pennsylvania
      • • Division of Gastroenterology
      • • Division of Endocrinology, Diabetes and Metabolism
      Philadelphia, Pennsylvania, United States
  • 2007–2011
    • Massachusetts General Hospital
      • Neuroendocrine Unit
      Boston, MA, United States
  • 2000–2011
    • Hospital of the University of Pennsylvania
      • • Department of Medicine
      • • Division of Endocrinology Diabetes and Metabolism
      • • Division of Gastroenterology
      Philadelphia, Pennsylvania, United States
  • 2006
    • The Children's Hospital of Philadelphia
      Philadelphia, Pennsylvania, United States
  • 2004
    • Albert Einstein College of Medicine
      New York City, New York, United States
  • 1996–2001
    • Beth Israel Deaconess Medical Center
      • • Department of Neurology
      • • Department of Medicine
      Boston, MA, United States
  • 1998–2000
    • Harvard Medical School
      • Department of Neurology
      Boston, MA, United States
  • 1992
    • Prince Henry's Institute
      Melbourne, Victoria, Australia
  • 1990–1992
    • Tulane University
      New Orleans, Louisiana, United States