Adipose, Aging, Behavior, Brain, Diabetes, Hormones, Insulin, Knockout Mice, Memory, Mitochondria, Neuro-degeneration/protection, Neurotoxicology, Obesity, Oxidative Stress, Transcription Factors, Transgenic Mice
PhD, University of Southern California
Specific Clinical/Research Interest:
Aging; obesity; diabetes; Alzheimer's disease; life extension; dietary restriction;
Current Students: Cesar Moreno(NEU); Stephanie Lum
Research Personnel: Instructor: Fumiko Isoda
Our laboratory studies the molecular basis of aging and age-related diseases, especially metabolic diseases such as obesity and diabetes, and related neurodegenerative diseases. Focusing on the interface between metabolic signals and the neurons that sense those signals and regulate metabolic processes, we have discovered several key molecular pathways that regulate energy balance and glucose homeostasis; impairments in these pathways constitute the main single-gene causes of obesity and diabetes in humans. We have extended discoveries in mammalian systems to the nematode C. elegans, discovering a transcriptional complex that mediates the protective effects of dietary restriction to increase lifespan and protect against age-related diseases, including Alzheimer-type pathology. Pharmacological activation of this pathway increases lifespan and protects against neurodegenerative diseases, and the same complex predicts lifespan and obesity in mice.
Summary of Research Studies:
Our laboratory uses histological, behavioral, electrophysiological, and molecular, methods (including DNA microarrays and RNA interference) to assess the basic mechanisms by which hypothalamic neurons sense and regulate metabolic state (including body weight and food intake), and how these mechanisms are impaired in metabolic diseases and during aging. A driving question of our laboratory is what may be called the metabolic mystery. This refers to the fascinating phenomenon that obesity is a risk factor for most age-related diseases and indeed for mortality, and conversely dietary restriction appears to slow down the aging process and extend maximum lifespan. Considering that almost all major pathologies are influenced by caloric intake, the mechanisms underlying the metabolic mystery may be considered among the most compelling in biomedical science. We really don't understand why caloric intake should lead to diseases, but many lines of evidence suggest neuroendocrine mech! anisms. We have begun to study the nature of the hypothalamic neurons which are sensitive to nutrition and which in turn regulate metabolic state, and we have thus begun to define a "nutritional field" of neurons which contain overlapping domains sensitive to different nutrients and which regulate different aspects of metabolism. Of particular interest is that the maximum overlap of these nutritional stimulation (e.g., glucose and leptin) may occur within the POMC neurons, which we now believe play a critical role in regulating metabolism. This is particularly interesting because the POMC neurons are among the most sensitive to decline during aging. To begin to directly test the role of specific gene products in the development of obesity, diabetes, and aging, we have now produced several lines of transgenic mice that overexpress leptin, POMC, insulin, and glucokinase specifically in the brain, and we are now assessing the effects of these transgenes in obesity, diabetes, an! d aging. For example, we have now shown that transgenic enhan! cement of neuronal POMC will completely correct the diabetes and other impairments in genetically obese mice. These studies have led to discovery of a new class of anti-obesity drugs that we are now studying. A new direction in our laboratory involves examining function of metabolic genes we have discovered using microarrays using RNA interference protocols in mice and in C. elegans. Using high-throughput RNAi screening methods we have discovered over 20 novel genes that regulate obesity in C. elegans. Using a similar approach we have also discovered a transcriptional complex that mediates the protective effects of dietary restriction to increase lifespan and protect against age-related diseases, including Alzheimer-type pathology and diabetic complications. Pharmacological activation of this pathway increases lifespan and protects against neurodegenerative diseases, and the same complex predicts lifespan and obesity in mice. We have now also developed novel high-throughput! methods to discover novel anti-obesity and anti-diabetes drugs, and have discovered over 20 drugs in each class so far.
Visit Dr. Charles Mobbs's Aging and Metabolism Lab for more information.
Ko F, Isoda F, Mobbs C. Laparotomy in Mice Induces Blood Cell Expression of Inflammatory and Stress Genes. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2014 Nov;.
Moreno C, Yang L, Dacks P, Isoda F, Poplawski M, Mobbs CV. Regulation of peripheral metabolism by substrate partitioning in the brain. Endocrinology and metabolism clinics of North America 2013 Mar; 42(1).
Mobbs CV, Moreno CL, Poplawski M. Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus. Trends in endocrinology and metabolism: TEM 2013 Oct; 24(10).
Kuz'menko VA. [Visuo-motor monitoring of physical strength during hyperthermia]. Fiziologiia cheloveka; 13(3).
Kim ES, Isoda F, Kurland I, Mobbs CV. Glucose-induced metabolic memory in Schwann cells: prevention by PPAR agonists. Endocrinology 2013 Sep; 154(9).
Yang L, Isoda F, Yen K, Kleopoulos SP, Janssen W, Fan X, Mastaitis J, Dunn-Meynell A, Levin B, McCrimmon R, Sherwin R, Musatov S, Mobbs CV. Hypothalamic Fkbp51 is induced by fasting, and elevated hypothalamic expression promotes obese phenotypes. American journal of physiology. Endocrinology and metabolism 2012 Apr; 302(8).
Schwartz E, Mobbs CV. Hypothalamic BDNF and obesity: found in translation. Nature medicine 2012 Apr; 18(4).
Dacks PA, Moreno CL, Kim ES, Marcellino BK, Mobbs CV. Role of the hypothalamus in mediating protective effects of dietary restriction during aging. Frontiers in neuroendocrinology 2013 Apr; 34(2).
Sato Y, Sato Y, Hayashi T, Shojima K, Kaji M. Cerebrospinal fluid ferritin in patients with central nervous system tumors. The Kurume medical journal 1985; 32(3).
Poplawski MM, Mastaitis JW, Isoda F, Grosjean F, Zheng F, Mobbs CV. Reversal of diabetic nephropathy by a ketogenic diet. PloS one 2011; 6(4).
Husa L, Bieger D, Fraser AF. Fluoroscopic study of the birth posture of the sheep fetus. The Veterinary record 1988 Dec; 123(25).
Diano S, Liu ZW, Jeong JK, Dietrich MO, Ruan HB, Kim E, Suyama S, Kelly K, Gyengesi E, Arbiser JL, Belsham DD, Sarruf DA, Schwartz MW, Bennett AM, Shanabrough M, Mobbs CV, Yang X, Gao XB, Horvath TL. Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nature medicine 2011 Sep; 17(9).
Riikonen R. Advances in therapy of infantile spasms. Current knowledge of actions of ACTH and corticosteroids. Brain & development 1987; 9(4).
Buckley MG, Sagnella GA, MacGregor GA. Plasma acidification increases atrial natriuretic peptide as measured by radioimmunoassay. Clinical chemistry 1987 Jun; 33(6).
Zhang M, Poplawski M, Yen K, Cheng H, Bloss E, Zhu X, Patel H, Mobbs CV. Role of CBP and SATB-1 in aging, dietary restriction, and insulin-like signaling. PLoS Biology 2009 Nov; 7(11).
Yen K, Mobbs CV. Isoforms play no role in lifespan in ad lib or dietary restricted conditions, but ablation of SOD-1 reduces life extension by cold. Mech. Age. and Dev 2008; In Press.
Yen K, Steinsaltz D, Mobbs CV. Validated analysis of mortality rates demonstrates distinct genetic mechanisms that influence lifespan. Exp Gerontol 2008 Sep 14;.
Yen K, Mobbs CV. Chemosensory and caloric mechanisms influence distinct components of mortality rate. Exp Gerontol 2008 Aug 28;.
Cheng H, Isoda F, Belsham D, Mobbs CV. Inhibition of AgRP expression by glucose in a clonal hypothalamic neuronal cell line is mediated by glycolysis, not oxidative phosphorylation. Endocrinology 2008; 149(2): 703-710.
Yang XJ, Mastaitis J, Mizuno T, Mobbs C. Glucokinase regulates reproductive function, glucocorticoid secretion, food intake, and hypothalamic gene expression. Endocrinology 2007; 104(7): 2501-2506.
Mizuno TM, Roberts J, Kelley K, Mobbs CV. Transgenic neuronal expression of proopiomelanocortin corrects insulin resistance in leptin-deficient but not diet-induced obesity . Diabetes 2003 Nov; 52(11): 2675-2683.
Mobbs CV. Reducing hypothalamic AGRP by RNA interference increases metabolic rate and decreases body weight without influencing food intake. BMC Neurosci. 2002; 7;3(1): 18.
Mizuno TM, Kleopoulos SP, Bergen H, Roberts JL, Priest CA, Mobbs CV. Rapid Communication: Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 1998; 47: 294-297.
Mizuno TM, Bergen H, Funabashi T, Kleopoulos SP, Zhong YG, Bauman WA, Mobbs CV. Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet- induced) and genetic (yellow agouti) obesity. Proc Natl Acad Sci U S A 1996; 93(8): 3434-3438.
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