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Understanding the genetic causes of obesity permits anticipatory guidance and targeted treatments. Children with hyperphagia and severe early-onset obesity should receive genetic testing for rare monogenic and syndromic disorders caused by pathogenic variants involving a single gene or single chromosomal region. Gene panels covering the leptin pathway, the key regulator of energy balance, are becoming more widely available and at lower cost. Polygenic obesity is much more common and involves multiple genes throughout the genome, although the overlap in genes for rare and common disorders suggests a spectrum of severity and the potential of shared precision medicine approaches for treatment., Competing Interests: Disclosures J.C. Han is a clinical trial investigator for multisite research studies sponsored by Rhythm Pharmaceuticals. The remaining authors have no disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Alström syndrome (AS) is a rare multisystem disorder of which early onset childhood obesity is a cardinal feature. Like humans with AS, animal models with Alms1 loss-of-function mutations develop obesity, supporting the notion that ALMS1 is required for the regulatory control of energy balance across species. This study aimed to determine which component(s) of energy balance are reliant on ALMS1., Methods: Comprehensive energy balance phenotyping was performed on Alms1 tvrm102 mice at both 8 and 18 weeks of age., Results: It was found that adiposity gains occurred early and rapidly in Alms1 tvrm102 male mice but much later in females. Rapid increases in body fat in males were due to a marked reduction in energy expenditure (EE) during early life and not due to any genotype-specific increases in energy intake under chow conditions. Energy intake did increase in a genotype-specific manner when mice were provided a high-fat diet, exacerbating the effects of reduced EE on obesity progression. The EE deficit observed in male Alms1 tvrm102 mice did not persist as mice aged., Conclusions: Either loss of ALMS1 causes a developmental delay in the mechanisms controlling early life EE or activation of compensatory mechanisms occurs after obesity is established in AS. Future studies will determine how ALMS1 modulates EE and how sex moderates this process., (© 2023 The Obesity Society.)

The TrkB receptor is critical for the control of energy balance, as mutations in its gene (NTRK2) lead to hyperphagia and severe obesity. The main neural substrate mediating the appetite-suppressing activity of TrkB, however, remains unknown. Here, we demonstrate that selective Ntrk2 deletion within paraventricular hypothalamus (PVH) leads to severe hyperphagic obesity. Furthermore, chemogenetic activation or inhibition of TrkB-expressing PVH (PVH TrkB ) neurons suppresses or increases food intake, respectively. PVH TrkB neurons project to multiple brain regions, including ventromedial hypothalamus (VMH) and lateral parabrachial nucleus (LPBN). We find that PVH TrkB neurons projecting to LPBN are distinct from those to VMH, yet Ntrk2 deletion in PVH neurons projecting to either VMH or LPBN results in hyperphagia and obesity. Additionally, TrkB activation with BDNF increases firing of these PVH neurons. Therefore, TrkB signaling is a key regulator of a previously uncharacterized neuronal population within the PVH that impinges upon multiple circuits to govern appetite.

Genetic evidence indicates that brain-derived neurotrophic factor (BDNF) signaling through the TrkB receptor plays a critical role in the control of energy balance. Mutations in the BDNF or the TrkB-encoding NTRK2 gene have been found to cause severe obesity in humans and mice. However, it remains unknown which brain neurons express TrkB to control body weight. Here, we report that TrkB-expressing neurons in the dorsomedial hypothalamus (DMH) regulate food intake. We found that the DMH contains both glutamatergic and GABAergic TrkB-expressing neurons, some of which also express the leptin receptor (LepR). As revealed by Fos immunohistochemistry, a significant number of TrkB-expressing DMH (DMH TrkB ) neurons were activated upon either overnight fasting or after refeeding. Chemogenetic activation of DMH TrkB neurons strongly suppressed feeding in the dark cycle when mice are physiologically hungry, whereas chemogenetic inhibition of DMH TrkB neurons greatly promoted feeding in the light cycle when mice are physiologically satiated, without affecting feeding in the dark cycle. Neuronal tracing revealed that DMH TrkB neurons do not innervate neurons expressing agouti-related protein in the arcuate nucleus, indicating that DMH TrkB neurons are distinct from previously identified LepR-expressing GABAergic DMH neurons that suppress feeding. Furthermore, selective Ntrk2 deletion in the DMH of adult mice led to hyperphagia, reduced energy expenditure, and obesity. Thus, our data show that DMH TrkB neurons are a population of neurons that are necessary and sufficient to suppress appetite and maintain physiological satiation. Pharmacological activation of these neurons could be a therapeutic intervention for the treatment of obesity., Competing Interests: The authors declare no conflict of interest.

Brain-derived neurotrophic factor (BDNF) is a key neuropeptide in the central regulation of energy balance. The Bdnf gene contains nine promoters, each producing specific mRNA transcripts that encode a common protein. We sought to assess the phenotypic outcomes of disrupting BDNF production from individual Bdnf promoters. Mice with an intact coding region but selective disruption of BDNF production from Bdnf promoters I, II, IV, or VI (Bdnf-e1 -/- , -e2 -/- , -e4 -/- , and -e6 -/- ) were created by inserting an enhanced green fluorescent protein-STOP cassette upstream of the targeted promoter splice donor site. Body composition was measured by MRI weekly from age 4 to 22 wk. Energy expenditure was measured by indirect calorimetry at 18 wk. Food intake was measured in Bdnf-e1 -/- and Bdnf-e2 -/- mice, and pair feeding was conducted. Weight gain, lean mass, fat mass, and percent fat of Bdnf-e1 -/- and Bdnf-e2 -/- mice (both sexes) were significantly increased compared with wild-type littermates. For Bdnf-e4 -/- and Bdnf-e6 -/- mice, obesity was not observed with either chow or high-fat diet. Food intake was increased in Bdnf-e1 -/- and Bdnf-e2 -/- mice, and pair feeding prevented obesity. Mutant and wild-type littermates for each strain (both sexes) had similar total energy expenditure after adjustment for body composition. These findings suggest that the obesity phenotype observed in Bdnf-e1 -/- and Bdnf-e2 -/- mice is attributable to hyperphagia and not altered energy expenditure. Our findings show that disruption of BDNF from specific promoters leads to distinct body composition effects, with disruption from promoters I or II, but not IV or VI, inducing obesity.

Brain-derived neurotrophic factor (BDNF) is a key regulator of energy balance; however, its underlying mechanism remains unknown. By analyzing BDNF-expressing neurons in paraventricular hypothalamus (PVH), we have uncovered neural circuits that control energy balance. The Bdnf gene in the PVH was mostly expressed in previously undefined neurons, and its deletion caused hyperphagia, reduced locomotor activity, impaired thermogenesis, and severe obesity. Hyperphagia and reduced locomotor activity were associated with Bdnf deletion in anterior PVH, whereas BDNF neurons in medial and posterior PVH drive thermogenesis by projecting to spinal cord and forming polysynaptic connections to brown adipose tissues. Furthermore, BDNF expression in the PVH was increased in response to cold exposure, and its ablation caused atrophy of sympathetic preganglionic neurons. Thus, BDNF neurons in anterior PVH control energy intake and locomotor activity, whereas those in medial and posterior PVH promote thermogenesis by releasing BDNF into spinal cord to boost sympathetic outflow., (Copyright © 2015 Elsevier Inc. All rights reserved.)