Adiposity, Chronic Disease
Risk and Aging: The potential
role of adipocyte lineage
Kathleen Gavin, PhD
Postdoctoral Fellow
Division of Geriatric Medicine
University of Colorado School of Medicine
Anschutz Medical Campus
Geriatric Medicine Grand Rounds
October 29, 2015
Outline
•
•
•
•
Adipose tissue – a role in chronic disease
Age related alterations in adiposity
Adipocyte development
Basic evidence for a novel adipocyte lineage
- bone marrow progenitor (BMP)-derived
adipocytes
• Evidence for BMP-derived adipocytes in
humans
• Conclusions
Adipose Tissue – A Fascinating Organ!
Extraordinary Capacity to Shrink or Expand
Lipodystrophy
Hypertriglyceridemia
Insulin Resistance
Hepatic Steatosis
Hypertrophic Cardiomyopathy
Obesity
Metabolic Syndrome
Type 2 Diabetes
Cardiovascular Disease
Pulmonary, Liver, and
Kidney disorders
Cancer
Canadian Obesity Network
Both extremes have serious
health consequences.
Body Fat Distribution and Disease Risk
Gesta, S. et al. Cell 131: 242-256, 2007
Why Does Adipose Tissue Differ by Depot?
Adipose Tissue Heterogeneity
•
Local Tissue Microenvironment:
– Local circulation
– Local innervation
– Non-adipocyte cell populations: preadipocytes, endothelial cells, pericytes,
multipotent stem cells, and various immune cells (macrophages, T-cells,
neutrophils, lymphocytes)
•
Genetically (or epigenetically) programmed developmental
differences in adipocytes and precursors.
– Adipocytes can retain depot-specific characteristics even when differentiated in
vitro (e.g., gene expression and insulin signaling).
(Perrini S, et al. 2009 Arch Physiol Biochem; Tchkonia T, et al. 2006 Diabetes; Tchkonia T,
et al. 2007 Am J Physiol Endocrinol Metab; Karastergiou K, et al. 2013 JCEM)
•
Distinct developmental pathways produce functionally distinct
adipocytes in different body locations (and maybe within adipose
depots).
Berry DC, et al. Development 140(19): 3939-3949, 2013
Changes in Body Composition with Age
↑ Adiposity and ↓ Fat-free mass
Chapman, IM. Interdiscip Top Gerontol. 37:20-36, 2010
Changes in Body Fat Distribution with Age
•
Inability to store fat
subcutaneously, particularly in
the lower body.
•
Lipid accumulation in nonsubcutaneous depots or in
lean tissue.
– ↑ visceral, liver, inter- and
intra-muscular, and other
‘ectopic’ fat depots.
•
Due, in part, to age related
dysregulation of lipid
metabolism in SQ
adipocytes?
•
Or, to age related
alterations in adipocyte
developmental pathways?
Kuk, JL, et al. Ageing Research Reviews 8(4):339-48, 2009
Geriatric Obesity Paradox
• Obesity (BMI ≥ 30 kg/m2) does not carry the same mortality
risk in older adults as younger adults.
• Association between BMI and mortality in older individuals is
neutral or inverse.
Relative risk of all-cause mortality across BMI categories,
stratified by age group, based on NHANES I, II and III data.
In Dixon, JB, et al. International Journal of Obesity 39, 82–84, 2015.
Adapted from: Flegal, KM, et al. JAMA. 293(15):1861–1867, 2005.
Identity of Adipocyte Progenitor Cells
• Mature adipocytes do not divide, so
new adipocytes must arise from a
precursor cell.
• Adipocyte turnover rate is ~10%/year in
humans (Spalding, K L, et al. Nature 453(7196): 783-787,
2008)
• Undifferentiated adipocyte precursor
cells have long been assumed to reside
and self-renew in stromal-vascular
fraction of the adipose tissue.
• Only in the last decade has some
convincing evidence been described for
the presence of distinct adipocyte
progenitor populations between
adipose depots.
(Majka, S. M., et al. Stem Cells 29(7): 1034-1040, 2011)
Adapted from Otto, TC & Lane, MD Crit Rev in Biochem & Mol Biol 40:229–242, 2005
Multipotent
mesenchymal
stem cell
Commitment
Preadipocyte
Differentiation factors
Clonal expansion
Contributes to hyperplasia
Differentiation
Mature
Adipocyte(s)
Hypertrophy
Other Sources of Adipocyte Progenitors:
What about bone marrow?
• Tissues throughout the body contain progenitor
cells capable of adipogenic differentiation.
• Including bone marrow - a rich source for both
mesenchymal and hematopoietic stem cells.
• Marrow mesenchymal cells do not enter the
circulation
– Hematopoietic cells do leave the marrow and traffic to
other tissues.
• Why couldn’t they traffic to adipose tissue and
become adipocytes?
Majka, SM, et al. Stem Cells 29:1034–1040, 2011
A subpopulation of adipocytes arises from bone
marrow (BM) progenitor cells – Basic Models
•
•
•
8 wk female wild type mice
Transplant: BM from adiponectin-cre LSL Luciferase mice
Whole body adipocyte production measured by in vivo imaging (Ivis System)
following injection with luciferin
16 weeks n=8; mean ± sd
Conclusions:
16 weeks
Gavin, KM. et al. FASEB J In Review
Accumulation of BMP-derived adipocytes:
• increases over time
• is present in major white adipose depots
of mice.
BMP-derived adipocytes are a sizable
component of the total adipocyte population.
Gonadal fat from female mouse transplanted with GFP-expressing BM
16 weeks post-transplant.
Within 8-16 wks BMP-derived adipocytes comprise
from 5-25% of total adipocyte pool depending on
gender, depot, time post transplant/birth.
Majka, SM, et al. Adipocyte 1: 215-229, 2012.
BMP-derived adipocytes are a distinct cell
population.
Principal component analysis
Majka, SM, et al. PNAS 107(33): 14781-14786, 2010
BMP-derived adipocytes exhibit decreased
expression of genes related to fuel oxidation
and mitochondrial/peroxisomal activity.
Cluster of 46 genes had 2.6 to 21 fold lower in BMPderived fat cells
Majka, SM, et al. PNAS 107(33): 14781-14786, 2010
BMP-derived adipocytes exhibit increased
expression of certain inflammatory and
chemotactic cytokine genes.
Hierarchical clustering
3.6 to 14 fold higher in BMP-derived fat cells
Majka, SM, et al. PNAS 107(33): 14781-14786, 2010
Ovarian hormones regulate the accumulation
of BMP-derived adipocytes.
α
Whole body luciferase
activity:
• is highest in the OVX
and αERKO mice
• is decreased by both
E2 and P add-back.
(all n=4)
Klemm, et al. Unpublished
*p<0.05 vs CON and OVX+E; all n=3.
Some adipocytes do arise from bone
marrow progenitors in mouse models.
BMP: bone marrow progenitor
Majka, SM, et al. PNAS 107(33): 14781-14786, 2010
Does this have clinical
relevance?
• Do BMP-derived adipocyte
accumulate in humans?
• Could their accumulation be a
mechanistic link underlying
adipose related chronic disease
risk?
Donor-derived adipocytes are present in
human adipose tissue from bone marrow
transplant (BMT) patients
Donor chimerism in adipocytes
9.875 ± 10.9% (range 0-35%)
Age
49.25 ± 16.7 yrs (range 24-75 yrs)
Post-transplant duration
2.145 ± 1.2 yrs (range 1-3.6 yrs)
Donor-derived adipocytes
accumulate over time
Linear
regression
R2 = 0.3074
R2 = 0.2332
Mean ± standard deviation
Blue, red, and green data points represent
values from participants with repeat biopsies
(7-12 months apart).
Gavin, KM, et al. FASEB J In Review
Conclusions
• Alternative development pathways for adipocytes exist (e.g.,
mesenchymal versus myeloid origin progenitors)
– Likely contribute to the functional diversity of distinct adipose
depots.
• Accumulation of BMP-derived adipocytes may be a
mechanism underlying adipose related chronic diseases in
humans.
– Explain some anomalies such as the obesity paradox in aging
(lower accumulation in people that live to older age)?
– Play a role in shifts in body fat distribution and elevated chronic
disease risk with the menopausal transition in women?
• Determining interventions to minimize the accumulation of
BMP-derived adipocytes may be important in future
preventative strategies for aging and/or adipose related
chronic disease.
Division of Geriatric Medicine
Acknowledgements
IMAGE Research Group
Mentors:
Funding:
•
Wendy Kohrt, PhD
•
Dwight Klemm, PhD
• K. Gavin: T32 AG000279, CCTSI CO-Pilot
Mentored Faculty Award, CCTSI Novel Methods
Pilot, F32 AG046957, UC Denver NORC Pilot
Award, Center for Women’s Health Research
•
Jonathan Gutman, MD
• D. Klemm: NIH R01 DK078966; GRECC Pilot
•
Karen Shea, MD
• W. Kohrt: NIH R21 DK092718, P50 HD073063
•
Klemm Laboratory
• NIH/NCATS Colorado CTSA Grant Number UL1
TR001082
–
Heidi Miller, Tim Sullivan and Paul Erickson
• NIH/NCI CCDG P30 CA046934
References
Berry DC, Stenesen D, Zeve D, and Graff JM. The developmental origins of adipose tissue. Development 140: 3939-3949, 2013.
Chapman IM. Obesity paradox during aging. Interdiscip Top Gerontol 37: 20-36, 2010.
Dixon JB, Egger GJ, Finkelstein EA, Kral JG, and Lambert GW. 'Obesity paradox' misunderstands the biology of optimal weight throughout the life cycle. Int J
Obes 39: 82-84, 2015.
Flegal KM, Graubard BI, Williamson DF, and Gail MH. Excess deaths associated with underweight, overweight, and obesity. JAMA 293: 1861-1867, 2005.
Gavin KM, Gutman JA, Kohrt WM, Wei Q, Shea KL, Miller HL, Sullivan TM, Erickson PF, Helm KM, Acosta AS, Childs CR, Musselwhite E, Varella-Garcia M,
Kelly K, Majka SM, and Klemm DJ. De novo generation of adipocytes from circulating progenitor cells in mouse and human adipose tissue. FASEB J In
Review.
Gesta S, Tseng YH, and Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell 131: 242-256, 2007.
Karastergiou K, Fried SK, Xie H, Lee MJ, Divoux A, Rosencrantz MA, Chang RJ, and Smith SR. Distinct developmental signatures of human abdominal and
gluteal subcutaneous adipose tissue depots. J Clin Endocrinol Metab 98: 362-371, 2013.
Kuk JL, Saunders TJ, Davidson LE, and Ross R. Age-related changes in total and regional fat distribution. Ageing Res Rev 8: 339-348, 2009.
Majka SM, Barak Y, and Klemm DJ. Concise review: adipocyte origins: weighing the possibilities. Stem Cells 29: 1034-1040, 2011.
Majka SM, Fox KE, Psilas JC, Helm KM, Childs CR, Acosta AS, Janssen RC, Friedman JE, Woessner BT, Shade TR, Varella-Garcia M, and Klemm DJ. De
novo generation of white adipocytes from the myeloid lineage via mesenchymal intermediates is age, adipose depot, and gender specific. Proc Natl Acad Sci U
S A 107: 14781-14786, 2010.
Majka SM, Miller HL, Sullivan T, Erickson PF, Kong R, Weiser-Evans M, Nemenoff R, Moldovan R, Morandi SA, Davis JA, and Klemm DJ. Adipose lineage
specification of bone marrow-derived myeloid cells. Adipocyte 1: 215-229, 2012.
Otto TC, and Lane MD. Adipose development: from stem cell to adipocyte. Crit Rev Biochem Mol Biol 40: 229-242, 2005.
Perrini S, Cignarelli A, Ficarella R, Laviola L, and Giorgino F. Human adipose tissue precursor cells: a new factor linking regulation of fat mass to obesity and
type 2 diabetes? Arch Physiol Biochem 115: 218-226, 2009.
Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Naslund E, Britton T, Concha H, Hassan M, Ryden M,
Frisen J, and Arner P. Dynamics of fat cell turnover in humans. Nature 453: 783-787, 2008.
Tchkonia T, Giorgadze N, Pirtskhalava T, Thomou T, DePonte M, Koo A, Forse RA, Chinnappan D, Martin-Ruiz C, von Zglinicki T, and Kirkland JL. Fat depotspecific characteristics are retained in strains derived from single human preadipocytes. Diabetes 55: 2571-2578, 2006.
Tchkonia T, Lenburg M, Thomou T, Giorgadze N, Frampton G, Pirtskhalava T, Cartwright A, Cartwright M, Flanagan J, Karagiannides I, Gerry N, Forse RA,
Tchoukalova Y, Jensen MD, Pothoulakis C, and Kirkland JL. Identification of depot-specific human fat cell progenitors through distinct expression profiles and
developmental gene patterns. Am J Physiol Endocrinol Metab 292: E298-307, 2007.
Vision for Future Research
Proof-ofConcept
Develop
Measurement
Tools
Utilize Tools in
Healthy
Humans
Long Term
Future
Directions
• Measure microchimerism of subcutaneous adipose tissue from bone marrow
transplantation patients
• Delineate/define specific lineage development pathway
• Identify and confirm biomarker for measurement in non-transplant humans
• Characterize gene expression fingerprint in human cells
• Determine metabolic phenotype (parallel gene expression fingerprint to murine models?)
• Determine region specific accumulation: subcutaneous vs. visceral, central vs. peripheral
• Are measurements of subcutaneous tissue an appropriate surrogate for visceral adipose?
• Determine triggers for accumulation: Aging, (loss of) sex hormones…
• Physiological consequences of accumulation, links to disease risk? Independent of
obesity?
• Test interventions that may help prevent accumulation (exercise, weight loss).
• New approach to evaluate the therapeutic impact of an intervention on metabolic risk?
Donor-derived Adipocytes Exist in Humans
Chimerism Results
Patient
Transplant
Type
Biopsy
#
Age at
Biopsy
(yr)
Posttransplant
(months)
Patients with Single Biopsy
1
2
3
4
5
Allogeneic
PBSC
Allogeneic
PBSC
Allogeneic
BM
Double
Cord Blood
Allogeneic
PBSC
Adipocyte
Chimerism
%
Donor
%
Recipient
1
63
12
<5
>95
1
75
12
11
89
1
45
14
11
89
1
24
18
0
100
1
33
48
35
65
59
60
54
55
41
42
28
35
31
43
43
53
5
13
<5
12
9
14
95
87
>95
88
91
86
Patients with Repeat Biopsy
6
Allogeneic
PBSC
7
Allogeneic
PBSC
8
Double Cord
Blood
1
2
1
2
1
2
PBSC = peripheral blood stem cells; BM = bone marrow.
Gavin, KM, et al. FASEB J In Review 2015