Mobbs Lab - Aging & Metabolism

Research

charles mobbOur laboratory studies the molecular basis of aging and age-related diseases, especially metabolic diseases such as obesity and diabetes, and related neurodegenerative diseases.

Contact Us

Mobbs Laboratory
Charles V Mobbs, PhD
Professor, Neuroscience
Location
Lab: ICAHN 9-26
Office: ICAHN 9-20F
Phone
Office: 212.659.5904
Lab: 212.659.5946
Email

What causes aging and age-related diseases, especially obesity, diabetes, and Alzheimer’s disease?

The metabolic mystery: obesity and diabetes (a surfeit of nutritional resources) accelerate many age-related diseases, and dietary restriction (a dearthof nutritional resources) slows down aging itself and almost all age-related diseases. What’s up with that?

Can we develop a drug to mimic all the protective effects of dietary restriction? (Yes!)

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 mechanisms. 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, and aging. For example, we have now shown that transgenic enhancement 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.

What is the hypothesis?

A key observation about the nature of age-related impairments is that these impairments accrue over time, reflecting a cumulative and apparently irreversible process. We have now discovered the molecular mechanism of this “molecular memory” effect and shown that it applies to all age-related diseases that are influenced by dietary restriction. In particular this process explains the cumulative development of diabetic complications, and implies that both age-related impairments and diabetic complications can not only be slowed (as with dietary restriction) but can actually be reveresed, by blocking glucose metabolism more effectively than can be done with dietary restriction. Further reading.

What are the projects?

Determine molecular mechanisms mediating the following observations:

AGING

Reversing aging by enhancing a novel CBP transcriptional complex
Reversing aging with a ketogenic diet.
Reversing aging by activating the “glucose-switch” gene pattern
Reversing age-dependent deleterious changes in gene expression

OBESITY

Reversing obesity and diabetes with a humanized FGFR1c receptor antibody.
Reversing obesity and diabetes caused by CtBP inhibition.
Reversing obesity and diabetes caused by CBP overexpression.
Reversing obesity and diabetes caused by CREB overexpression.
Reversing obesity and diabetes with a ketogenic diet.
Reversing obesity and diabetes by inhibiting hypothalamic genes that predict obesity.
Reversing obesity by inhibiting hypothalamic genes whose inhibition reverses obesity in C. elegans
Reversing obesity in mice by drugs that reverse glucose-dependent obesity in C. elegans.

DIABETES

Reversing diabetic complications with drugs that block glucose neurotoxicity
Reversing diabetic complications with a ketogenic diet

ALZHEIMER’S DISEASE

Reversing Alzheimer’s disease with drugs that prevent neurodegeneration.
Reversing Alzheimer’s disease by enhancing a novel CBP transcriptional complex
Extending lifespan and preventing age-related diseases by enhancing activity of a novel CBP transcriptional complex.

What are the protocols?

In mice

  • Genetic engineering (transgenic and knockout)
  • Genetic manipulation by in vivo gene transfer: AAV and nanoparticles
  • Complete metabolic phenotyping:
    • Food intake
    • Activity
    • Metabolic rate (indirect calorimetery)
    • Temperature telemetry
  • Tissue analysis

C. elegans

    • Lifespan analysis
    • Oxidative stress
    • Obesity
  • Functional screen by high-throughput RNAi

In cell culture

  • Viability
  • High-content analysis
  • Metabolic pathways
  • Gene expression (RT-PCR)

Featured

Featured Publication

Ko F, Isoda F, Mobbs C. Laparotomy in Mice Induces Blood Cell Expression of Inflammatory and Stress Genes. Journal of interferon & cytokine research.  2015 Apr;35(4):302-12. doi: 10.1089/jir.2014.0031. Epub 2014 Nov 19.

Surgical trauma induces immune and stress responses although its effects on postsurgical inflammatory and stress gene expression remain poorly characterized. This study sought to improve current scientific knowledge by investigating the effects of laparotomy on mouse blood cell inflammatory and stress gene expression.

Publications

2015

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. doi: 10.1089/jir.2014.0031. PubMed PCMID: 25406893

2013

Mobbs CV, Moreno CL, Poplawski M. Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus. Trends Endocrinol Metab. 2013. doi: 10.1016/j.tem.2013.05.007. PubMed PMID: 23791973; PubMed Central PMCID: 23791973.


Mobbs CV, Moreno C. Hypothalamic EphA5 Facilitates Counterregulatory Responses: Possible Role for Bidirectional Signaling Leading to Bistability That Enhances Responsiveness to Hypoglycemia. Diabetes. 2013;62(4):1014-6. Epub 2013/03/23. doi: 62/4/1014 [pii]10.2337/db12-1735. PubMed PMID: 23520275; PubMed Central PMCID: 3609568.


Kim ES, Isoda F, Kurland I, Mobbs CV. Glucose-induced metabolic memory in Schwann cells: prevention by PPAR agonists. Endocrinology. 2013;154(9):3054-66. doi: 10.1210/en.2013-1097. PubMed Central PMCID: 23709088.


Moreno C, Yang L, Dacks P, Isoda F, Poplawski M, Mobbs CV. Regulation of peripheral metabolism by substrate partitioning in the brain. Endocrinol Metab Clin North Am. 2013;42(1):67-80. doi: 10.1016/j.ecl.2012.11.007. PubMed Central PMCID: 23391240.


Dacks PA, Moreno CL, Kim ES, Marcellino BK, Mobbs CV: Role of the hypothalamus in mediating protective effects of dietary restriction during aging. Front Neuroendocrinol published online, 2013


Kefaloyianni E, Lyssand JS, Moreno C, Delaroche D, Hong M, Fenyo D, Mobbs CV, Neubert TA, Coetzee WA: Comparative proteomic analysis of the ATP-sensitive K(+) channel complex in different tissue types. Proteomics 13:368-378, 2013


Mobbs C, Mastatits J, Isoda F, Poplawski M: Treatment of diabetes and diabetic complications with a ketogenic diet. Journal of Child Neurology (in press), 2013


Mobbs C, Moreno C, Poplawski M: Metabolic mystery: Aging, obesity, diabetes and ventromedial hypothalamus. Trends Endocrinol Metab (in press), 2013


Mobbs CV, Moreno C: Hypothalamic EphA5 facilitates counterregulatory responses: Possible role for bi-directional signaling leading to bi-stability that enhances responsiveness to hypoglycemia. Diabetes (in press), 2013


Moreno C, Yang L, Dacks P, Isoda F, Poplawski M, Mobbs C: Regulation of Peripheral Metabolism by Substrate Partitioning in the Brain. Endocrinol Metab Clin North Am 42:67-80, 2013

2012

Yang L, Isoda F, Yen K, Kleopoulos SP, Janssen W, Fan X, Mastaitis J, Dunn-Meynell A, Levin BE, McCrimmon R, Sherwin R, Musatov S, Mobbs CV. Hypothalamic Fkbp51 is induced by fasting and elevated hypothalamic expression promotes obese phenotypes. Am J Physiol Endocrinol Metab. 2012. Epub 2012/02/10. doi: ajpendo.00474.2011 [pii] 10.1152/ajpendo.00474.2011. PubMed Central PMCID: 22318949.


Schwartz E, Mobbs CV. Hypothalamic BDNF and obesity: found in translation. Nat Med. 2012;18(4):496-7. Epub 2012/04/07. doi: nm.2716 [pii] 10.1038/nm.2716. PubMed Central PMCID: 22481407.


Dacks PA, Moreno CL, Kim ES, Marcellino BK, Mobbs CV. Role of the hypothalamus in mediating protective effects of dietary restriction during aging. Front Neuroendocrinol. 2012. Epub 2012/12/25. doi: S0091-3022(12)00063-5 [pii]10.1016/j.yfrne.2012.12.001. PubMed Central PMCID: 23262258.


Moreno C, Yang L, Dacks P, Isoda F, Poplawski M, Mobbs CV. Regulation of peripheral metabolism by substrate partitioning in the brain. Endocrinol Metab Clin North Am. 2013;42(1):67-80. doi: 10.1016/j.ecl.2012.11.007. PubMed Central PMCID: 23391240.


Schwartz E, Mobbs CV: Hypothalamic BDNF and obesity: found in translation. Nat Med 18:496-497, 2012


Yang L, Isoda F, Yen K, Kleopoulos SP, Janssen W, Fan X, Mastaitis J, Dunn-Meynell A, Levin BE, McCrimmon R, Sherwin R, Musatov S, Mobbs CV: Hypothalamic Fkbp51 is induced by fasting and elevated hypothalamic expression promotes obese phenotypes. Am J Physiol Endocrinol Metab, 2012

Mobbs C, Moreno C, Kim E, Ekasumara N, Marcellino B: Neuroprotection by dietary restriction and the Ppar transcription complex. Translational Neuroscience 3:234-241, 2012

2011

Poplawski MM, Mastaitis JW, Mobbs CV. Naloxone, but not valsartan, preserves responses to hypoglycemia after antecedent hypoglycemia: role of metabolic reprogramming in counterregulatory failure. Diabetes. 2011;60(1):39-46. Epub 2010/09/03. doi: db10-0326 [pii]10.2337/db10-0326. PubMed Central PMCID: 3012195.


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):e18604. Epub 2011/05/03. doi: 10.1371/journal.pone.0018604. PubMed Central PMCID: 21533091.

Lublin A, Isoda F, Patel H, Yen K, Nguyen L, Hajje D, Schwartz M, Mobbs C. FDA-Approved Drugs that Protect Mammalian Neurons from Glucose Toxicity Slow Aging Dependent on Cbp and Protect Against Proteotoxicity. PLoS One. 2011;6(11):e27762. Epub 2011/11/25. doi: 10.1371/journal.pone.0027762PONE-D-11-16976 [pii].; PubMed Central PMCID: 3218048.


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. Nat Med. 2011;17(9):1121-7. Epub 2011/08/30. doi: nm.2421 [pii]10.1038/nm.2421. Central PMCID: 21873987.

2010

Yen K, Mobbs CV. Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans. Age (Dordr). 2010;32(1):39-49. Epub 2009/08/08. doi: 10.1007/s11357-009-9110-7. 19662517; PubMed Central PMCID: 2829647.


Poplawski MM, Mastaitis JW, Yang XJ, Mobbs CV. Hypothalamic responses to fasting indicate metabolic reprogramming away from glycolysis toward lipid oxidation. Endocrinology. 2010;151(11):5206-17. Epub 2010/10/01. doi: en.2010-0702 [pii] 10.1210/en.2010-0702. PubMed Central PMCID: 2954726.

Meet the Team

Fumiko Isoda

Fumiko Isoda

Postdoctoral Fellow

efumiko.isoda@mssm.edu

Stephanie Lum

Stephanie Lum

Student

stephanie.lum@mssm.edu

Cesar Moreno

Cesar Moreno

Student

cesar.moreno@mssm.edu

About Dr. Mobbs

EDUCATION

B.S. Biology 1978
Massachusetts Institute of Technology, Cambridge, MA

Ph.D. Cell/Molecular Biology 1984
Univ. of Southern California
Mentor: Caleb Finch, Ph.D.

POSTDOCTORAL TRAINING

NIH Post-doctoral fellowship 1984-1988
Rockefeller University, NY
Mentor: Donald Pfaff, Ph.D.

Grant and Contract Support

Source, Number, Title Dates
Current Support
American Diabetes Association, “Role of endogenous opioid system in impaired responses to hypoglycemia” 08/01/12 – 07/31/15
Diabetes Action Foundation, “Prevention and reversal of diabetic neuropathy by a ketogenic diet” 01/01/15 – 02/31/16
4D program for translational research, “High-throughput protocols to screen for drugs to treat Alzheimer’s disease” 10/01/08 – 09/30/11
Recent Past
NIH/NIDDK, “Protective role of creb-binding protein in maturation and aging” 07/01/08 – 06/30/11
NIH/NIDDK “Hypothalamic glucokinase in obesity and diabetes” 07/01/09 – 03/31/11
JDRF, “Reversal of counterregulatory failure with valsartan” 07/01/13 – 06/30/14
JDRF, “Prevention and epigenetic mechanisms of metabolic memory” 07/01/13 – 06/30/14
Klarman Foundation, “Role of Hypothalamic Metabolism in Estrogen‐induced Anorexia” 07/01/09 – 06/30/11
NIH/NIDDK, “Novel hypothalamic molecular mechanisms for disorders of energy balance and glucose homeostasis” 07/01/09 – 06/30/10
HONORS
1974:  National Merit Scholar
1974:  Chancellor Scholar (Texas Christian University)
1975:  McDermott Scholar (MIT)
1979:  Best Teaching Assistant Award (USC)
1981, 1983:  Sigma Xi Graduate Student Research Award
1982:  George Sacher Award, Best Student Paper (Gerontol. Soc.)
1985:  Grass Fellowship, Cold Spring Harbor Laboratory
1989:  Glenn Foundation Fellow
1993:  Mentor, Brookdale Foundation
2005:  Ellison Medical Foundation Senior Fellow
2010: Outstanding mentorship, Mount Sinai School of Medicine
2012: Glenn Award for Research in Biological Mechanisms of Aging

SERVICE
1988: National Academy of Sciences Committee on Aging
1990-1994: Editorial Board, Mechanisms of Aging and Development
1992-1996: Research and Development Committee, VAMC
1992-1996: Institutional Animal Review Committee, VAMC
1992-1996: Co-director, Molecular Diagnostics Core Lab, VAMC
1994-present: Reviewer, American Federation for Aging Research
1997-present: Co-founder of Annual Endocrinology of Aging Symposium
1996-present: Co-editor, “Interdisciplinary Topics in Gerontology”, Karger 1999-2004: Endocrinology Study Section, NIH (Ad hoc)
2002-2004: Metabolism Study Section, NIH (Ad Hoc)
2002-2005: Canadian Institute of Nutrition, Metabolism and
Diabetes Review Committee (Ad Hoc)
2004-2006: Cellular Aspects of Diabetes and Obesity Study Section (Ad Hoc)
2004-2006: Integrated Physiology of Obesity and Diabetes (CADO) (Ad Hoc)
2003: Panel on Complications, Juvenile Diabetes Foundation (JDFI)
2003-present: Scientific Review Committee, Juvenile Diabetes Foundation
2005-2008: Medical Review Committee American Diabetes Association
2005-2009: Editorial Board, Endocrinology 2005-present: Editorial Board, Endocrinology
(Official journal of the Endocrine Society)
2006-present: Editorial Board, Obesity Research
2006-present: Associate Editor, Obesity and Metabolism
2006-2008: Integrated Physiology of Obesity and Diabetes (Charter)
2006-2009: Steering Committee, Endocrine Society
2006-2009: Endocrine Society Steering Committee
2008-present: Special Emphasis Study Sections
2005-2009: Interventions Testing Program Access Committee, NIA
2009-2017: Chair, Interventions Testing Program Access Committee, NIA

Neurobiology of Aging, Responsible Conduct in Research, Others
Neuroscience of Aging
Drug Discovery
Integrated metabolism
Basic Biology of Aging
Foundations of Biomedical Research