Arcuate Nucleus-Specific Leptin Receptor Gene Therapy Attenuates the Obesity Phenotype of Koletsky (fak/fak) Rats

Abstract

Leptin signaling in the hypothalamic arcuate nucleus (ARC) is hypothesized to play an important role in energy homeostasis. To investigate whether leptin signaling limited to this brain area is sufficient to reduce food intake and body weight, we used adenoviral gene therapy to express the signaling isoform of the leptin receptor, lepr(b), in the ARC of leptin receptor-deficient Koletsky (fa(k)/fa(k)) rats. Successful expression of adenovirus containing lepr(b) (Ad-lepr(b)) selectively in the ARC was documented by in situ hybridization. Using real-time PCR, we further demonstrated that bilateral microinjection of Ad-lepr(b) into the ARC restored low hypothalamic levels of lepr(b) mRNA to values approximating those of wild-type (Fa(k)/Fa(k)) controls. Restored leptin receptor expression in the ARC reduced both mean daily food intake (by 13%) and body weight gain (by 33%) and increased hypothalamic proopiomelanocortin mRNA by 65% while decreasing neuropeptide Y mRNA levels by 30%, relative to fa(k)/fa(k) rats injected with a control adenovirus (Ad-lacZ) (P < 0.05 for each comparison). In contrast, Ad-lepr(b) delivery to either the lateral hypothalamic area of fa(k)/fa(k) rats or to the ARC of wild-type Fa(k)/Fa(k) rats had no effect on any of these parameters. These findings collectively support the hypothesis that leptin receptor signaling in the ARC is sufficient to mediate major effects of leptin on long-term energy homeostasis. Adenoviral gene therapy is thus a viable strategy with which to study the physiological importance of specific molecules acting in discrete brain areas.

Acute anorexigenic action of leptin in rainbow trout is mediated by the hypothalamic Pi3k pathway

“…LEP is anorexigenic in mammals, and this central action of LEP on appetite and energy balance is mediated through the dorsomedial, ventromedial, ventral premamillary and arcuate nuclei (ARC) of the mediobasal hypothalamus, where the full-length functional LEP receptor (LEPRb) is highly expressed (Elmquist et al 1998, Morton et al 2003. In the ARC, LEP inhibits the gene expression of the orexigenic neuropeptide Y (NPY) and agouti-related peptide (AGRP), and stimulates the expression of the anorexigenic proopiomelanocortin (POMC) and cocaine-and amphetamine-regulated transcript (CART) (Kristensen et al 1998, Bates et al 2003, Morrison et al 2005.…”

Formation of Projection Pathways from the Arcuate Nucleus of the Hypothalamus to Hypothalamic Regions Implicated in the Neural Control of Feeding Behavior in Mice

“…Leptin receptors are expressed in the ARH (Elmquist et al, 1998a) and it contains high densities of neurons that express Fos protein and SOCS-3 mRNA after intravenous injection of leptin (Elias et al, 1998(Elias et al, , 2000Elmquist et al, 1998b). Lesions of the ARH result in leptin insensitivity (Choi et al, 1999), and viral transfection of leptin receptor into ARH neurons alone is sufficient to cause reductions in food intake in leptin receptor-deficient rats (Morton et al, 2003). From the ARH, leptin signals appear to be distributed through neural projections to other sites implicated in the control of feeding, such as the paraventricular nucleus of the hypothalamus (PVH), the dorsomedial hypothalamic nucleus (DMH), and the lateral hypothalamic area (LHA) (Elias et al, 1998Elmquist et al, 1998b).…”

Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice

“…Deletion of leptin receptors in the CNS recapitulates the effects of leptin deficiency on metabolic homeostasis (6). In addition, several studies have found that selective perturbation of leptin action within populations of medial basal hypothalamic neurons accounts for some of the effects of leptin in the regulation of energy balance (7)(8)(9)(10)(11). For example, leptin receptor deletion in proopioid melanocortin (POMC) arcuate neurons and steroidogenic factor 1 neurons in the ventromedial hypothalamus (VMH) produces modest obesity (7,10).…”