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Hypothalamic POMC deficiency increases circulating adiponectin despite obesity.
Authors Yu H, Chhabra KH, Thompson Z, Jones GL, Kiran S, Shangguan G, Low MJ
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Molecular metabolism
Year 2020
Date Published 5/1/2020
Volume : Pages 35 : 100957
PubMed Reference 32244188
Abstract The steep rise in the prevalence of obesity and its related metabolic syndrome
have become a major worldwide health concerns. Melanocortin peptides from
hypothalamic arcuate nucleus (Arc) POMC neurons induce satiety to limit food
intake. Consequently, Arc Pomc-deficient mice (ArcPomc-/-) exhibit hyperphagia
and obesity. Previous studies demonstrated that the circulating levels of
adiponectin, a protein abundantly produced and secreted by fat cells, negatively
correlate with obesity in both rodents and humans. However, we found that
ArcPomc-/- mice have increased circulating adiponectin levels despite obesity.
Therefore, we investigated the physiological function and underlying mechanisms
of hypothalamic POMC in regulating systemic adiponectin levels., Circulating
adiponectin was measured in obese ArcPomc-/- mice at ages 4-52 weeks. To
determine whether increased adiponectin was a direct result of ArcPomc
deficiency or a secondary effect of obesity, we examined plasma adiponectin
levels in calorie-restricted mice with or without a history of obesity and in
ArcPomc-/- mice before and after genetic restoration of Pomc expression in the
hypothalamus. To delineate the mechanisms causing increased adiponectin in
ArcPomc-/- mice, we determined sympathetic outflow to adipose tissue by
assessing epinephrine, norepinephrine, and tyrosine hydroxylase protein levels
and measured the circulating adiponectin in the mice after acute norepinephrine
or propranolol treatments. In addition, adiponectin mRNA and protein levels were
measured in discrete adipose tissue depots to ascertain which fat depots
contributed the most to the high level of adiponectin in the ArcPomc-/- mice.
Finally, we generated compound Adiopoq-/-:ArcPomc-/- mice and compared their
growth, body composition, and glucose homeostasis to the individual knockout
mouse strains and their wild-type controls., Obese ArcPomc-/- female mice had
unexpectedly increased plasma adiponectin compared to wild-type siblings at all
ages greater than 8 weeks. Despite chronic calorie restriction to achieve normal
body weights, higher adiponectin levels persisted in the ArcPomc-/- female mice.
Genetic restoration of Pomc expression in the Arc or acute treatment of the
ArcPomc-/- female mice with melanotan II reduced adiponectin levels to control
littermate values. The ArcPomc-/- mice had defective thermogenesis and decreased
epinephrine, norepinephrine, and tyrosine hydroxylase protein levels in their
fat pads, indicating reduced sympathetic outflow to adipose tissue. Injections
of norepinephrine into the ArcPomc-/- female mice reduced circulating
adiponectin levels, whereas injections of propranolol significantly increased
adiponectin levels. Despite the beneficial effects of adiponectin on metabolism,
the deletion of adiponectin alleles in the ArcPomc-/- mice did not exacerbate
their metabolic abnormalities., In summary, to the best of our knowledge, this
study provides the first evidence that despite obesity, the ArcPomc-/- mouse
model has high circulating adiponectin levels, which demonstrated that increased
fat mass is not necessarily correlated with hypoadiponectinemia. Our
investigation also found a previously unknown physiological pathway connecting
POMC neurons via the sympathetic nervous system to circulating adiponectin,
thereby shedding light on the biological regulation of adiponectin.


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