A Central Thermogenic-like Mechanism in Feeding Regulation: An Interplay between Arcuate Nucleus T3 and UCP2

Abstract

The active thyroid hormone, triiodothyronine (T3), regulates mitochondrial uncoupling protein activity and related thermogenesis in peripheral tissues. Type 2 deiodinase (DII), an enzyme that catalyzes active thyroid hormone production, and mitochondrial uncoupling protein 2 (UCP2) are also present in the hypothalamic arcuate nucleus, where their interaction and physiological significance have not been explored. Here, we report that DII-producing glial cells are in direct apposition to neurons coexpressing neuropeptide Y (NPY), agouti-related protein (AgRP), and UCP2. Fasting increased DII activity and local thyroid hormone production in the arcuate nucleus in parallel with increased GDP-regulated UCP2-dependent mitochondrial uncoupling. Fasting-induced T3-mediated UCP2 activation resulted in mitochondrial proliferation in NPY/AgRP neurons, an event that was critical for increased excitability of these orexigenic neurons and consequent rebound feeding following food deprivation. These results reveal a physiological role for a thyroid-hormone-regulated mitochondrial uncoupling in hypothalamic neuronal networks.

Melanocortin-3 receptor regulates the normal fasting response

“…5 B and C). Previous work had suggested that the rise in NPY and AgRP resulted from a local increase in T3 production because of increased expression of deiodinase 2 (DIO2) (23). Fasting-induced up-regulation of DIO2 also is aberrant in the MC3-R −/− mouse (Fig.…”

“…Fasting-induced refeeding is also impaired in the NPY −/− , DIO2 −/− , and uncoupling protein 2 (UCP2) −/− mice (23,50,51). Interestingly, a single pathway has been proposed to be responsible for the altered fasting-induced refeeding in the NPY-, DIO2-, and UCP2-knockout models.…”

“…Interestingly, a single pathway has been proposed to be responsible for the altered fasting-induced refeeding in the NPY-, DIO2-, and UCP2-knockout models. Coppola et al (23) elegantly describe a pathway whereby arcuate nucleus glial cells convert T4 to T3 via DIO2. T3 induces mitochondrial upregulation of UCP2 in NPY neurons, thereby increasing their activity and increasing feeding drive.…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…Thyroid hormone exhibits a number of effects that are mediated directly at the medial basal hypothalamus. An example is the increase in food intake that rapidly follows administration of T 3 directly into the ventromedial nucleus (514)(515)(516). A related approach is to implant T 3 crystals stereotaxically into discrete hypothalamic areas.…”

Exercise-Induced Synaptogenesis in the Hippocampus Is Dependent on UCP2-Regulated Mitochondrial Adaptation

“…One of these mitochondrial proteins, UCP2, is found in the CNS and has been implicated in various neuronal mechanisms (Andrews et al, 2005a). We and others have shown that UCP2 is involved in neuroprotection in mice models of Parkinson's disease (Andrews et al, 2005b;Conti et al, 2005), epilepsy , and stroke (Mattiasson et al, 2003) as well as in normal functioning of the nigrostriatal dopamine system (Andrews et al, 2006) and the arcuate nucleus melanocortin system (Coppola et al, 2007;Andrews et al, 2008). Induction of UCP2 expression in the brain by cellular stress increases the overall production of ATP, perhaps as a result of stimulation of mitochondrial proliferation, while decreasing superoxide production and associated damage Diano et al, 2003, Andrews et al, 2005b.…”