A potential link between dorsomedial hypothalamic nucleus NPY and energy balance

Abstract

The function of dorsomedial hypothalamic neuropeptide Y in energy balance has largely been restricted to lactation-induced hyperphagia. In this issue, Chao et. al (2011) expand this role to include inhibition of both brown fat thermogenesis and conversion of white-to-brown adipocytes in a white fat depot, resulting in reduced energy expenditure.

The study of the role of the dorsomedial hypothalamus (DMH) in energy balance in rodents began in 1963 by Lee Bernardis and associates who found that large electrolytic lesions in areas of the DMH in young laboratory rats resulted in stunted growth and decreased eating and drinking (Bernardis et al., 1963). Interestingly, more refined lesions selectively destroying only the DMH showed these same effects, along with normal body composition (Bellinger and Bernardis, 2002). This prompted extensive studies aimed at understanding the mechanistic underpinnings of these changes [for historical review of DMH lesions see: (Bellinger and Bernardis, 2002)]. More recently, the DMH has been heavily implicated in BAT thermogenesis and energy expenditure [for review see: (DiMicco and Zaretsky, 2007)]. One of the neurochemicals present in the DMN is neuropeptide Y (NPY). Overexpression of NPY in the DMH via an AA resulted in enhanced food intake, body weight and exaggerated diet-induced obesity in normal weight rats (Yang et al., 2009). In this issue (2011), Chao and colleagues used a recombinant vector of AAV-mediated RNAi targeting NPY to test the metabolic consequences of the selective knockdown (KD) of DMH NPY in rats.

This KD was effective (~50% DMH NPY 2–4 wk after injection), specific (arcuate unaffected) and long lasting (16 wk, but then ~35% decrease). There was a small decrease in body weight of DMH NPY KD rats versus controls when fed regular chow (~20% for the first 5 wks); a similar effect was found with a HFD, but KD rats exhibited a less pronounced and shorter duration of HFD-induced hyperphagia. In addition, DMH NPY KD improved glucose homeostasis, insulin sensitivity and decreased HFD-induced increases in blood glucose and insulin. The authors did not determine a mechanism for these later changes, but they could be due to an effect of reduced DMH NPY on pancreatic/liver function or perhaps were secondary to increased energy expenditure resulting in decreased body fat thereby improving insulin sensitivity and reducing blood glucose.

Most interesting and perhaps most important was their observation that only the inguinal white adipose tissue (IWAT) of DMH NPY KD rats displayed a brown adipocyte phenotype -- the so-called ‘brite’ or ‘beige’ cells. IWAT was visibly brown with sizable islands of multilocular cells were immunoreactive for the established brown adipocyte marker uncoupling protein-1 (UCP-1), the mitochondrial protein responsible for heat generation. Both Western blot and RT-PCR showed increased IWAT and interscapular BAT UCP-1 protein and mRNA, supporting the histological evidence. IWAT in KD rats also expressed increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha mRNA, which is associated with mitochondrial biogenesis, enhanced BAT thermogenic programming, and white-to-brown transdifferentiation of adipocytes (Barbatelli et al., 2010). Finally, there also was an increase in IWAT carnitine palmitoyltransferase Ia mRNA, suggestive of a transition to lipid oxidation rather than storage (Chao et al., 2011).

Chronic WAT sympathetic nervous system (SNS) activation triggered by long-term cold exposure or ß3-adrenergic receptor agonist treatment (Barbatelli et al., 2010) induces brown adipocyte formation in WAT (Cousin et al., 1992). The present study also suggests that the presence of brite/beige cells in IWAT of DMH NPY KD rats was mediated by SNS innervation of this tissue. Specifically, injecting the noradrenergic toxin, 6-hydroxy-dopamine unilaterally in IWAT to achieve a local, selective, and chemical sympathetic WAT denervation (Rooks et al., 2005) resulted in an effective/selective IWAT sympathectomy accompanied by a blocked or attenuated ability to develop a brown fat phenotype relative to the contralateral, neurologically intact IWAT pad. This suggests that DMH NPY might normally curb the remodeling of IWAT to a BAT-like phenotype. The brown adipocytes could have arisen from myoblasts that express a ‘molecular switch’ [PRDM16 and C/EBP-beta; (Kajimura et al., 2009)], the presence of which turns them ‘brown’; another possibility is transdifferentiation of white-to-brown adipocytes via chronic stimulation of ß₃-adrenoceptors (Barbatelli et al., 2010). The authors discount this latter possibility because histologically intermediate stages of transdifferentiation, the so-called paucilocular adipocytes, were not observed. Their absence, however, does not necessarily discount transdifferentiation because the change may already have occurred during this prolonged (16 wk) treatment. A time course study should resolve this issue.

We demonstrated the CNS origins of the SNS outflow from the brain to WAT using the transneuronal viral tract tracer, pseudorabies virus [PRV; (Bamshad et al., 1998)]. In that study, injection of this retrogradely traveling trans-synaptic tract tracer resulted in more PRV-labeled cells in the DMH after IWAT than after epididymal WAT (EWAT) injection (Bamshad et al., 1998). Based on the above findings, Chao and colleagues considered a potential neuroanatomical basis for the selectivity of DMH manipulation that hinged on the apparent preferential DMH SNS outflow to IWAT versus EWAT. Therefore, because differential SNS drive among WAT depots seems to be the norm rather than the exception [for review see: (Bartness et al., 2010)], perhaps there is greater SNS drive to IWAT (and IBAT) than other WAT pads, thereby promoting the white-to-brown transdifferentiation.

DMH NPY KD produced several indications that the observed histological, genetic and protein surrogates of increased thermogenesis reflect energetically relevant behavioral and physiological consequences. These rats displayed exaggerated nocturnal locomotor activity, increased energy expenditure (indirect calorimetry), but normal body temperature, the latter not surprising because it is controlled by multiple redundant regulatory mechanisms. DMH NPY KD rats did, however, exhibit a greater increase in body temperature during acute cold exposure than controls.

Collectively, the data of Chao et al. (2011) suggest that decreased DMH NPY affects a suite of factors impinging on energy balance including increased energy expenditure perhaps via enhanced BAT and WAT (brite/beige adipocytes), improved glucose tolerance/insulin sensitivity, and blocked HFD-induced increases in circulating glucose and insulin. The selective nature of the increase in IWAT brite/beige adipocytes via SNS innervation is likely due to chronic increases in SNS drive thereby activating ß₃-adrenoceptors and triggering transdifferentiation of white-to-brown adipocytes, and/or possibly increases in these cells from myoblast precursors. Whether naturally-occurring decreases in DMH NPY can unmask WAT brownness or whether, in some sense, this is a genetic trick, is not known. Key to determining this is to establish which environmental/physiological conditions promote such changes. If this can occur naturally, then decreased DMH NPY may protect some animals from increased adiposity and/or it could be somehow exploited pharmacologically to help reverse obesity.