Effects of Intracerebroventricular Administration of Neuropeptide Y on Metabolic Gene Expression and Energy Metabolism in Male Rats
Endocrine Society
Received February
Effects of Intracerebroventricular Administration of Neuropeptide Y on Metabolic Gene Expression and Energy Metabolism in Male Rats
Yan Su 0
Ewout Foppen 0
Eric Fliers 0
Andries Kalsbeek 0
0 Hypothalamic Integration Mechanisms (Y.S., A.K.), Netherlands Institute for Neuroscience , 1105 BA Amsterdam , The Netherlands; and Department of Endocrinology and Metabolism (E.Fo.,E.Fl., A.K.), Academic Medical Center, University of Amsterdam , 1105 AZ Amsterdam , The Netherlands
Neuropeptide Y (NPY) is an important neurotransmitter in the control of energy metabolism. Several studies have shown that obesity is associated with increased levels of NPY in the hypothalamus. We hypothesized that the central release of NPY has coordinated and integrated effects on energy metabolism in different tissues, resulting in increased energy storage and decreased energy expenditure (EE). We first investigated the acute effects of an intracerebroventricular (ICV) infusion of NPY on gene expression in liver, brown adipose tissue, soleus muscle, and sc and epididymal white adipose tissue (WAT). We found increased expression of genes involved in gluconeogenesis and triglyceride secretion in the liver already 2-hour after the start of the NPY administration. In brown adipose tissue, the expression of thermogenic genes was decreased. In sc WAT, the expression of genes involved in lipogenesis was increased, whereas in soleus muscle, the expression of lipolytic genes was decreased after ICV NPY. These findings indicate that the ICV infusion of NPY acutely and simultaneously increases lipogenesis and decreases lipolysis in different tissues. Subsequently, we investigated the acute effects of ICV NPY on locomotor activity, respiratory exchange ratio, EE, and body temperature. The ICV infusion of NPY increased locomotor activity, body temperature, and EE as well as respiratory exchange ratio. Together, these results show that an acutely increased central availability of NPY results in a shift of metabolism towards lipid storage and an increased use of carbohydrates, while at the same time increasing activity, EE, and body temperature. (Endocrinology 157: 3070 -3085, 2016) Abbreviations: AR, adrenoceptor; BAT, brown adipose tissue; BW, body weight; EE, energy expenditure; eWAT, epididymal WAT; Gapdh, glyceraldehyde 3-phosphate dehydrogenase; Hprt, hypoxanthine guanine phosphoribosyl transferase; ICV, intracerebroventricular; NPY, neuropeptide Y; RER, respiratory exchange ratio; sMuscle, soleus muscle; SNS, sympathetic nervous system; sWAT, sc WAT; Tbp, TATA box-binding protein; TG, triglyceride; 3V, third ventricle; UCP, uncoupling protein; VCO2, CO2 production; VO2, O2 consumption; WAT, white adipose tissue.
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Ntide, which is widely expressed in the central (
1
) and
europeptide Y (NPY) is a 36-amino acid
neuropepperipheral nervous system (
2
). In the brain, NPY is found
in many brain areas (
3
), including the hypothalamus,
dentate gyrus, lateral thalamus, and striatum, with highest
concentrations in the arcuate nucleus of the
hypothalamus. NPY is the most potent orexigenic neuropeptide
known thus far. The stimulatory effect of NPY on feeding
is seen after intracerebroventricular (ICV) infusion of
NPY in the lateral (
4
) and third ventricle (3V) (
5
), as well
as after local infusion in specific brain areas (
6, 7
),
including the paraventricular nucleus of the hypothalamus (8),
the lateral hypothalamus (
7
), the nucleus accumbens (
9
),
and the ventral tegmental area (
9
). Administration of NPY
into the hypothalamus or ventricular system also strongly
affects energy metabolism, because it increases hepatic
glucose production (
10, 11
), triglyceride production (12),
white adipose tissue (WAT) lipoprotein lipase activity
(
13
), while decreasing hepatic insulin sensitivity (
10, 11
)
and thermogenesis (
13–15
). These findings clearly show
that central administration of NPY has profound
metabolic effects throughout the body. Together, these data
indicate that the coordinated action of NPY is to promote
energy storage and decrease energy expenditure (EE).
One characteristic of obesity is the excessive intake,
synthesis and storage of lipids as fat. This overproduction
of fat is associated with increased lipogenesis in different
organs, such as liver and WAT (
16, 17
). Several studies
found that obesity is associated with elevated levels of NPY
in the hypothalamus (
18 –22
). Therefore, it has been
speculated that a derangement of the hypothalamic NPY system
may play an important role in the development of obesity.
However, most of the studies investigating the effects of NPY
reported on isolated observations in single organs instead of
whole body effects in all major metabolic organs.
Liver, WAT, brown adipose tissue (BAT), and muscle
are important organs when it comes to the regulation of
energy metabolism. A disturbance of metabolic processes,
such as thermogenesis (...truncated)