An appetite for cilia
Could obesity be a ciliopathy, a
disorder caused by tiny microtubule
bundles that protrude from every
cell in the hypothalamus?
O
extra toes and fingers to cystic kidneys,
blindness, and mental deficits. Obesity is a
characteristic symptom of BBS. An animal
“model” of the syndrome is available: a
mouse genetically modified to lose primary
cilia on neurons. Unable to regulate its
feeding behavior, the BBS model mouse
becomes obese. The UAB team used this
mouse model to explore the relationship
between cilia defects, obesity, and leptin
signaling in the brain. The researchers
noticed that mice with the mutation lose
leptin sensitivity when obese but saw the
mice regain leptin sensitivity as their diet
was restricted and their weight fell to normal levels. But which was the cause and
which the effect? And did primary cilia have
any role in this response?
Berbari reports that leptin insensitivity in BBS and cilia-mutant mice models is
a secondary consequence of their obesity
and not a causal factor. Instead, the researchers began to look at other potential
appetite-regulating pathways. During
earlier research in the laboratory of Kirk
Mykytyn, Berbari showed that the melaninconcentrating hormone (MCH) receptor,
another player in appetite regulation, localizes in primary cilia in normal brain cells
that regulate feeding behavior. However, in
the BBS mice, the UAB researchers found
that the MCH receptor could not enter the
cilium. Preliminary experiments suggest
that the MCH signaling pathway is altered
in cilia mutants. This research underscores
the role primary cilia may play in obesity,
says Berbari, who also believes that unraveling the complex signaling roles of primary cilia will lead to a better understanding
of how they shape other human behaviors,
including learning, memory, and mood.
besity is a modern plague affecting
populations in the developed and
developing world alike. A “silver bullet” cure is unlikely because researchers still
struggle with understanding how appetite is
regulated. Consider the peptide leptin, for
example, a fat-produced hormone that acts
in a region of the brain called the hypothalamus to suppress appetite. So in theory, add
leptin, stifle appetite, and then lose weight.
But it’s not that simple, as new data
from Nicolas Berbari, Brad Yoder, and colleagues at the University of Alabama at Birmingham (UAB) make clear. These researchers are coming at this complex problem from
a new direction looking at obesity as a possible consequence of defects in leptin signaling and the activity of primary cilia.
Microscopic hairlike structures that extend outward from the cell, cilia come in two
classes. There are motile cilia, which beat
in rhythmic waves, sweeping airways clean.
Then there are the immotile, or primary,
cilia, which until recently were thought to
have little clinical significance. Primary
cilia protrude, one to a cell, from virtually every cell type in vertebrates. No one
took primary cilia seriously until defects in
them were implicated as a possible cause of
polycystic kidney disease, a life-threatening
genetic disorder. Soon, primary cilia began
to emerge as sensors for a variety of extracellular signals and defects. Research linked
them to so many human diseases and conditions that a term was coined to cover them:
ciliopathies. One condition now associated
with a subgroup of
ciliopathy patients is
morbid obesity.
The connection
between cilia and
obesity is evident in
humans with Bardet–
Biedl syndrome (BBS),
a rare genetic disorder
traced to defects in
proteins that function
in primary cilia. BBS
patients display a range
of symptoms—from
LEFT: Cilia Mutant Obese Mice: An obese mouse (right) that has lost its cilia throughRIGHT: Ciliated Cultured Neuron: Cultured hypothalamic neuron (neuronal marker
β-Tubulin III in green) with a Mchr1 positive cilium (red).
A m er ica n
s o c i e t y
fo r
C e ll
B i o l o g y | The American Society
for Cell Biology
51st Annual Meeting
Denver, Colorado
December 3–7, 2011
EMBARGOED
FOR RELEASE
10:00 am, U.S. Mountain Time
Tuesday, December 6, 2011
Contact
Nicolas F. Berbari, PhD
Department of Cell Biology
University of Alabama
at Birmingham
1918 University Blvd.
Birmingham, AL 35294
205-934-0995
[email protected]
Author presents
Tuesday, December 6, 2011
2:00 pm–3:30 pm
Session: Cilia and Flagella III
Presentation: 1450
Board Number: B172
Exhibit Halls: A/B/E/F
Primary Cilia in Appetite
and Satiety
N. F. Berbari,1 R. C. Pasek,1
E. B. Malarkey,1 S. M. Yazdi,1
A. D. McNair,1 R. A. Kesterson,2
T. R. Nagy,3 B. K. Yoder1
1 Cell Biology, University of
Alabama at Birmingham,
Birmingham, AL
2 Genetics, University of
Alabama at Birmingham,
Birmingham, AL
3 Nutrition Sciences, University
of Alabama at Birmingham,
Birmingham, AL
Nick Berbari’s research is
funded by the National Institutes of Health (NIH), NIDDK
grant F32 DK088404. Brad
Yoder is supported through
NIH-NIDDK grant R01
DK075996.
out the central nervous system (left) next to a wild-type littermate.
The
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