Fat Metabolite Inhibits Feeding Response

        Fat is the primary long-term energy storage molecule in animals, and the control of fat levels is critical for survival. In mammals, the hormone leptin induces eating in response to fat loss, but so far, no corresponding signal has been identified, either in mammals or any other animal, that inhibits eating in response to fat gain.

        Adipose tissue is never truly a welcome thought for most people, yet at the cellular level, it acts as the primary site of energy storage for the body. While scientists have often surmised that there must be some level of communication between adipose tissue and the brain, to regulate feeding behavior and monitor the energy reserves, the underlying molecular mechanisms are poorly understood. However now, a team of researchers at the Korea Advanced Institute of Science and Technology (KAIST) has just published data identifying a molecule in fruit flies sent by fat cells to the fly brain that senses when they have had enough food and inhibits feeding.

        Findings from the new study—published recently in PLOS Biology in an article entitled “A Fat-Derived Metabolite Regulates a Peptidergic Feeding Circuit in Drosophila”—has wide implications not only for weight loss but could also be beneficial for stimulating appetite and weight gain for a variety of disease with wasting-associated symptoms. 

        In the current study, the investigators focused their sights on short noncoding RNAs or microRNAs (miRNAs), which are well-known inhibitors of gene expression. They first searched for miRNAs that, when overexpressed in fat tissue, affected feeding behavior, and second for the gene targets of those miRNAs. The research team identified a miRNA called miR-iab-4, which increased feeding by more than 27% and targeted a Drosophila gene called purple, which was expressed in fat bodies.

        Reducing purple expression enhanced feeding, suggesting its normal function was to inhibit it. Purple is known to be one of two fat-body enzymes that build a molecule called PTP, or 6-pyruvoyltetrahydropterin, which is released by fat bodies and circulates in the fly brain. There, a third enzyme converts PTP into a well-known enzyme cofactor, called tetrahydrobiopterin (BH4).

        “We perform a targeted genetic screen in Drosophila melanogaster and identify a role for the enzymatic cofactor tetrahydrobiopterin (BH4) in regulating ad libitum feeding behavior in fruit flies,” the authors wrote. “We show that three highly conserved enzymes—Punch, Purple, and Sepiapterin Reductase (Sptr)—are required for the biosynthesis of BH4. Fat body-specific knock-down of either Punch or Purple increases feeding, and this increase can be rescued by BH4.”

        Previous research has shown that BH4 is required in the neurons that produce neuropeptide F (NPF), which regulates feeding. In the current study, the authors showed that loss of purple in the fat body, or loss of BH4 in neurons, led to increased release of NPF and increased feeding. Conversely, increasing BH4 in neurons reduced NPF release and decreased feeding. Finally, they showed that feeding flies a low-calorie diet reduced expression of the fat body enzymes that control BH4 production and led to increased feeding.

        These new study results suggest that BH4 plays a key role in suppressing appetite in flies and that PTP released from fat bodies delivers a signal to the brain indicating that energy stores are sufficient and that feeding can stop. While these results apply only to flies currently, the identification of this appetite-suppression mechanism will surely spur research into related pathways in humans.

    “Our study indicates fat tissue sends a molecular signal to the fly brain to regulate feeding behavior,” concluded senior study investigator Walton Jones, Ph.D., assistant professor at KAIST. “Further studies will be needed to determine if a similar system acts in mammals, and if so, whether it can be safely manipulated to help achieve weight loss, or gain, in people.”