In recent years, studies have shown that bone
is an endocrine organ and produces hormones that affect brain
development, glucose balance, kidney function, and male fertility.
A hormone secreted by bone cells can suppress appetite, according to
mouse studies conducted by Columbia University Medical Center (CUMC)
‘The bone hormone - called lipocalin 2 - turns on neurons in the brain that have been previously linked to appetite suppression.’
The hormone - called lipocalin 2 - turns on neurons in the
brain that have been previously linked to appetite suppression. The
findings reveal a previously unknown mechanism for regulating the body's
energy balance and could lead to new targeted therapies for the
treatment of obesity, type 2 diabetes, and other metabolic disorders.
The study was published online today in the journal Nature
Study leader Stavroula Kousteni, associate professor of physiology
and cellular biophysics (in medicine) at CUMC, said, "Our findings add a
critical new function of bone hormones to this list - appetite
suppression - which may open a wholly new approach to the treatment of
In 2007, a CUMC team led by Gerard Karsenty, the Paul A.
Marks Professor of Genetics and Development and professor of medicine,
and chair, Department of Genetics and Development at CUMC, was the first
to discover that bone is an endocrine organ that regulates energy
metabolism through the release of a hormone called osteocalcin. "We
hypothesized that there were additional bone hormones that regulate
metabolism, since other endocrine organs that affect metabolism usually
do so through multiple hormones," said Dr. Kousteni.
The first clues to a second hormone came in 2010, when Dr. Kousteni
discovered that disabling a gene called FOXO1 in mouse osteoblasts
(bone-forming cells) caused the mice to eat less and improved their
glucose balance. "Since osteocalcin does not regulate appetite, we knew
that a second bone hormone had to be involved in this process," said Dr.
In the current study, the CUMC researchers demonstrated that
FOXO1-deficient osteoblasts express unusually high amounts of a protein
called lipocalin 2. Lipocalin 2 was previously thought to be primarily
secreted by adipocytes (fat cells) and to contribute to obesity. But the
researchers showed, using mice that could not produce lipocalin in
either their fat cells or osteoblasts, that lipocalin 2 is primarily
secreted by osteoblasts and reduces appetite and weight.
Lipocalin 2 also affected appetite and weight in normal-weight mice
and in mice that were obese due to a lack of the leptin receptor and
leptin signalling. In both types of mice, lipocalin 2 suppressed
appetite, improved overall metabolism, and reduced body weight.
Dr. Kousteni and her team also found that lipocalin 2 crosses the
blood-brain barrier. In the brain, the protein binds to and activates
melanocortin 4 receptor (MC4R) neurons in the hypothalamus, the primary
brain region that regulates appetite. MC4R neurons are known to be
involved in triggering appetite suppression.
"The hope is that lipocalin 2 might have the same effects in
humans, and that our findings can be translated into the development of
therapies for obesity and other metabolic disorders," said Dr. Kousteni.
Initial findings in humans are encouraging. In an analysis of
patients with type 2 diabetes, the researchers found that blood levels
of lipocalin 2 were inversely correlated with body weight and blood A1c
levels, a long-term measure of blood sugar. "In other words, patients
with higher lipocalin 2 levels had lower body weight and better glucose
balance," said Dr. Kousteni.