Melanocortin 4 Receptor-Mediated Hyperphagia and Activation of Neuropeptide Y Expression in the Dorsomedial Hypothalamus during Lactation

Abstract

In several hyperphagic models, including lactation, in which hypothalamic melanocortin signaling is reduced, a novel expression of NPY mRNA in the dorsomedial hypothalamus (DMH) has been observed, suggesting that melanocortin signaling and the induced NPY in the DMH may constitute unique neurocircuitry in mediating energy balance. Using lactating rats as a model, the present study first showed that in the DMH abundant ␣-MSH and agouti-related protein fibers are in close apposition to NPY-positive cells. However, no NPY and MC4R (a melanocortin receptor) double-labeled neurons were observed. These data suggested that melanocortin input may synapse on presynaptic terminals that then synapse on DMH NPY cells. To study the function of DMH MC4Rs in energy balance, an MC3/4R-selective agonist, melanotan II (MTII), was injected bilaterally into the DMH. MTII injection significantly suppressed feeding induced by 24 hr fasting or suckling-induced hyperphagia. Furthermore, MTII treatment greatly attenuated suckling-induced NPY expression in the DMH. MTII treatment also stimulated uncoupling protein 1 activity in the brown adipose tissue of suckling female rats, indicative of increased sympathetic outflow. In summary, the present study demonstrated that the melanocortin system in the DMH not only plays an important role in inducing NPY expression in the DMH of lactating rats but also in regulating energy homeostasis, at least in part, by modulating appetite and energy expenditure.

Plasticity in gastrointestinal morphology and enzyme activity in lactating striped hamsters (Cricetulus barabensis)

“…In the present study, AgRP mRNA expression was significantly up-regulated in striped hamsters raising larger litter sizes, whereas NPY, POMC and CART mRNA expression did not differ between the hamsters raising different litter sizes. This is partly consistent with the observation that in lactating rats, both NPY and AgRP are greatly elevated (Chen et al, 2004;Crowley et al, 2004;Li et al, 1999;Malabu et al, 1994;Pickavance et al, 1999;Smith, 1993;Suzuki et al, 2014), but the increase in AgRP mRNA expression during lactation is especially marked (Suzuki et al, 2014). POMC and/or CART mRNA expression significantly decreased during lactation in comparison with the non-lactation period (Brogan et al, 2000;Smith, 1993;Sorensen et al, 2002;Suzuki et al, 2014).…”

“…The neuroendocrine basis of hyperphagia in lactation is suggested to be triggered by hypothalamic neuropeptides, such as the orexigenic neuropeptides NPY and AgRP, and the anorexigenic neuropeptides POMC and CART (Brogan et al, 2000;Chen et al, 2004;Crowley et al, 2004;Malabu et al, 1994;Li et al, 1999;Pickavance et al, 1999;Smith, 1993;Sorensen et al, 2002;Suzuki et al, 2014). In the present study, AgRP mRNA expression was significantly up-regulated in striped hamsters raising larger litter sizes, whereas NPY, POMC and CART mRNA expression did not differ between the hamsters raising different litter sizes.…”

Adaptation to lactation in OLETF rats lacking CCK-1 receptors: body weight, fat tissues, leptin and oxytocin

“…8,46 DMH NPY has been shown to be important in modulating lactation-associated hyperphagia. 14 In male OLETF rats, NPY mRNA is overexpressed in the DMH, suggested a primary deficit in NPY signaling that may contribute to their hyperphagia and obesity. 22 In response to long-term exercise, DMH NPY was overexpressed in LETO but not in OLETF male rats.…”

“…12,13 During lactation, the amount of hypothalamic neuropeptide Y (NPY) increases 8 mainly in the DMH. 14 In Western society, the incidences of overweight and obesity are increasing. Weight gain during pregnancy and lactation has many implications for women's and children's health, including risks related to adult obesity.…”

Induction of Brain Region-Specific Forms of Obesity by Agouti

“…For example, single injections of MC4-R ligands in the PVN alter food intake and body weight in rodents (Kim et al, 2000;Wirth et al, 2001). Recent studies suggest that the dorsal medial hypothalamus (DMH) is also involved in the regulation of hyperphagia (Chen et al, 2004). In addition, based on the outcome of classical lesion, electric stimulation, and electrophysiological studies, the lateral hypothalamus (LH) has long been implicated in the regulation of energy metabolism (Anand and Brobeck, 1951;Delgado and Anand, 1953;Katafuchi et al, 1985).…”