Leptin signaling regulates hypothalamic expression of nescient helix-loop-helix 2 (Nhlh2) through signal transducer and activator 3 (Stat3)

Abstract

Mice with a deletion of the hypothalamic basic helix-loop-helix transcription factor Nhlh2 display adult onset obesity. We have previously shown that Nhlh2 expression is induced by leptin. In this study, we identify a small proximal leptin-responsive promoter region in the Nhlh2 gene. This 163 bp promoter contains five putative binding sites for the leptin-activated Stat3 transcription factor, and two putative binding sites for the NFκB transcription factor. Results of mutagenesis studies reveal that deletion of the NFκB sites have little effect, mutagenesis of the third Stat3 site eliminates both leptin-induced and basal expression of Nhlh2. Mutagenesis of the 4th and 5th sites eliminates leptin-induced expression, and increases basal expression above the WT promoter. Stat3 can be preferentially pulled down from leptin-treated mouse hypothalamic chromatin extracts. This study identifies leptin-induced Stat3 transcription factor as the major transcriptional regulator of Nhlh2. As Nhlh2 transcriptionally regulates genes within the melanocortin pathway, these findings have implications for human body weight control.

Maternal gestational weight gain and objectively measured physical activity among offspring

“…In animal studies, maternal obesity and overfeeding have been directly linked to hypothalamic leptin resistance, reduced leptin signalling, and altered hypothalamic neurodevelopment towards orexigenic pathways [ 50 ], each having been associated with regulation of PA [ 51 ]. Hypothalamic leptin resistance could also affect an individual’s PA by down-regulating nescient helix-loop-helix 2 ( Nhlh2 ) transcription factor [ 52 ]. Nhlh2 has been associated with increased spontaneous PA and voluntary exercise in mice possibly by increasing one’s motivation to exercise by up-regulating b-endorphin and/or dopamine levels [ 53 ].…”

An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation

“…Leptin signaling in the hypothalamus proopiomelanocortin neurons depends on the nerve growth factor Nur77, which subsequently activates signal transducer and activator of transcription 3 ( Stat3 ) [86]. The downstream STAT3-activated nescient helix-loop-helix 2 in leptin signaling pathway is required for transcriptional activation of proopiomelanocortin processing enzyme proprotein convertase 1 [87]. Most importantly, STAT3 binds to the cis -regulatory elements on proopiomelanocortin promoter together with SP1 to activate its transcription and diet-induced leptin resistance was usually associated with impaired STAT3 signaling cascade in proopiomelanocortin neurons [66, 88, 89].…”

A molecular conundrum involving hypothalamic responses to and roles of long non-coding RNAs following food deprivation

“…The N2KO mice were developed nearly 20 years ago, and are characterized by adult-onset obesity, as well as reduced physical activity levels 82 . Furthermore, Nhlh2 itself is a target of energy availability pathways, such as fasting, cold-exposure and leptin signaling 83–85 . In fact, our previous finding on leptin-induced Nhlh2 expression through Signal transducer and activator of transcription 3 (Stat3) rather than Nuclear factor kappa B (NFKB) indicates a possible indirect regulation of Nhlh2 expression by lncRNAs due to the fact that the transcriptional activity of both Stat3 and NFKB can be regulated by lncRNAs 50,86–88 .…”