Role of the arcuate nucleus of the hypothalamus in regulation of body weight during energy deficit

Abstract

Acute or long-term energy deficit in lean or obese rodents or humans stimulates food intake or appetite and reduces metabolic rate or energy expenditure. These changes contribute to weight regain in post-obese animals and humans. Some studies show that the reduction in metabolic rate with energy deficit in overweight people is transient. Energy restriction has been shown in some but not all studies to reduce physical activity, and this may represent an additional energy-conserving adaptation. Energy restriction up-regulates expression of the orexigenic neuropeptide Y, agouti related peptide and opioids and down-regulates that of the anorexigenic alpha-melanocyte stimulating hormone or its precursor pro-opioomelanocortin and the co-expressed cocaine and amphetamine-regulated transcript in the arcuate nucleus of the hypothalamus. Recapitulating these hypothalamic changes in sated animals mimics the effects of energy deficit, namely increased food intake, reduced physical activity and reduced metabolic rate, suggesting that these energy-conserving adaptations are at least partially mediated by the hypothalamus.

Effects of energy restriction on activity of the hypothalamo-pituitary-adrenal axis in obese humans and rodents: implications for diet-induced changes in body composition

“…Another factor that could contribute to the discrepant findings reported in this section is negative feedback regulation of the HPA axis; initial increases in circulating cortisol levels can feed back on the pituitary gland and hypothalamus and lead to eventual normalization or even inhibition of the axis. Support for this concept comes from a study involving continuous central administration of neuropeptide Y to rats [62], an experimental paradigm that mimics many aspects of energy restriction [63]. This paradigm initially increased circulating corticosterone and ACTH concentrations, but subsequently led to normalization of these parameters, as well as down-regulation of hypothalamic CRH mRNA expression [62].…”

Central neuropeptide Y infusion and melanocortin 4 receptor antagonism inhibit thyrotropic function by divergent pathways

“…NPY-AgRP and POMC-expressing neurons in the arcuate nucleus project to the paraventricular nucleus (PVN) (Baker andHerkenham, 1995 andO'Donohue et al, 1979), where they exert stimulatory (NPY and AgRP) (Stanley et al, 1985 andClark et al, 1984) or inhibitory (α-MSH) (Thiele et al, 1998 andBrown et al, 1998) effects on food intake. During energy restriction in rodents, the protein or mRNA levels of NPY and AgRP are increased in the hypothalamus whereas the mRNA expression of proopiomelanocortin is reduced (Sainsbury and Zhang, 2010). This change likely has important effects on the hypothalamopituitary thyroid axis, as NPY, AgRP, and α-MSH-containing neuronal endings have been detected in close association with neurons in the PVN that synthesize thyrotropin-releasing hormone (TRH) in rodents (Legradi and Lechan, 1999) and in humans .…”

“…Overweight or obese people who lost weight by moderate or severe energy restriction (with or without physical activity) showed significant decreases in circulating concentrations of the most active thyroid hormone free triiodothyronine (T3) and/or a significant increase in that of the inactive hormone, reverse T3, as well as significant reductions in circulating concentrations of thyroid stimulating hormone (TSH) and free thyroxine (T4), the precursor to T3 (Hukshorn et al, 2003a, Hukshorn et al, 2003b, Rosenbaum et al, 2000, Weinsier et al, 2000, Wadden et al, 1990, Naslund et al, 2000and Douyon and Schteingart, 2002. As thyroid hormones are major regulators of energy expenditure, acting on peripheral tissues to directly influence cellular metabolism (Silva, 2003) as well as on hypothalamic sites to regulate AMP-activated protein kinase, fatty acid metabolism and subsequent sympathetic nervous output , reduced thyroid function likely contributes to the concomitant reduction in metabolic rate or energy expenditure (Weinsier et al, 2000, Rosenbaum et al, 1997, Leibel et al, 1995, WesterterpPlantenga et al, 2001, Westerterp-Plantenga et al, 2004, Hukshorn et al, 2003a, Hukshorn et al, 2003b, Menozzi et al, 2000, Martin et al, 2007and Sainsbury and Zhang, 2010. The weight loss-induced drop in energy expenditure is a significant predictor of weight regain (Pasman et al, 1999 andGoran, 2000), so insights into mechanisms for decreased thyroid function and energy expenditure could lead to improved weight loss interventions.…”

Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice

“…This is due -at least in part -to weight loss activating adaptive responses that stimulate appetite and reduce energy expenditure, as recently reviewed . These adaptive responses to energy restriction are seemingly mediated by numerous hypothalamic peptides Zhang, 2010 and, notably neuropeptide Y (NPY) (Stephens et al, 1995) and possibly also the opioid peptides, dynorphins Kalra, 1996 andSainsbury et al, 2007), with the aforementioned drug, Contrave, utilising opioid receptor antagonism as one of its mechanisms of action.…”

“…These responses are associated with significant decreases in total energy expenditure and body temperature (Hwa et al, 1999), along with increases in food efficiency and fat accretion (Stanley et al, 1986). These effects of NPY contribute to obesity in rodents when leptin action is permanently reduced , and conceivably also contribute to body weight regain in people after lifestylebased weight loss interventions Zhang, 2010 and. Therefore, it would follow on that blocking the effects of increased hypothalamic NPYergic tonus, thus blocking these adaptive responses to energy restriction, could increase the effectiveness of weight loss interventions.…”