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Open research questions in Regulation of Appetite and Obesity

48 unresolved questions extracted from the limitations and future-work sections of 373 Regulation of Appetite and Obesity papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • It remains unclear whether acupuncture forms an efficient positive feedback loop by altering peripheral adipose tissue signals, integrating and amplifying them through the central nervous system, and subsequently regulating peripheral metabolism. Although the detailed biological structure and function of lipid droplets are not yet fully understood, the rapid advancement of lipidomics and matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry (MALDI-TOF-IMS) promises to elucidate the mechanisms by which acupuncture affects lipid drop- lets (Fig. The changes in lipid droplets during acupuncture regulation of lipid metabolism are still unknown, and whether the expression levels of lipid droplet proteins are affected by acupuncture has not been studied.

    Advances in the “Neuro-endocrine-Adipose” Axis Mediated by Acupuncture for Lipid Metabolism Regulation · 2026 · DOI

  • Neurons in the lateral hypothalamus that express the neuropeptide neurotensin (LH-Nts neurons) are known to influence many of these elements, but their precise role in regulating specific aspects of ingestive behavior remains unclear.

    Multidimensional control of ingestive behavior by lateral hypothalamic neurotensin neurons · 2026 · DOI

  • A minimum 6-day washout was incorporated between treatment periods to minimise carryover, but because the absorption and elimination profile of TRPTI had not been previously characterised in humans, residual biological or physiological carry-in effects between the placebo and 150 mg visits cannot be entirely excluded. Therefore, longer-duration trials incorporating enzymatic activity measures and validated appetite assessments are warranted.

    Acute TRPTI™ (oleoylethanolamide) supplementation enhances incretin hormone responses: a fixed-sequence crossover study · 2026 · DOI

  • Aging-related decline in hematopoietic and platelet function is a hallmark of DNA repair deficiency syndromes, yet the impact of metabolic and pharmacological interventions on platelet biology in this context remains unclear.

    Therapeutic Effect of Myostatin/Activin Blockage and Dietary Restriction in Modulation of Platelet Activation Markers of Progeroid Mouse Model · 2026 · DOI

  • The AP also mediates much of the satiety produced by GLP1R agonists, suggesting a broader role in non-aversive physiology, yet the functions of AP cell types are not well understood.

    Functional segregation of body-brain signals in the area postrema · 2026 · DOI

  • Although exogenous CCK has been reported to induce thermogenesis in intrascapular brown adipose tissue (iBAT), whether this effect depends on vagal pathways and specific central circuits remains incompletely understood.

    Peripheral cholecystokinin promotes thermogenesis via vagal afferent signalling, hypothalamic oxytocin and sympathetic outflow to brown adipose tissue · 2026 · DOI

  • Within the VMH, neurons expressing steroidogenic factor-1 (SF-1; VMH SF1 ) are essential for regulating energy expenditure, yet the projection-defined pathways through which they differentially control distinct adipose depots remains unclear.

    Projection-defined hypothalamic outputs differentially regulate thermogenesis and lipolysis · 2026 · DOI

  • The ghrelin-LEAP2 system has emerged as a central regula- tory system coordinating energy balance, glucose homeo- stasis, and behavioural responses to nutritional status [91, 194, 206, 221, 260, 261]. By integrating peripheral meta- bolic signals with hypothalamic neuroendocrine circuits, ghrelin and its endogenous antagonist LEAP2 dynamically regulate feeding behaviour, glucose counter-regulation, and metabolic adaptation to fasting and nutrient availability. Disruption of this balance contributes to the pathophysiol- ogy of obesity, T2D, and maladaptive feeding behaviours, positioning the ghrelin-LEAP2 system as a biologically compelling yet complex therapeutic target [113, 161]. Despite substantial advances in understanding ghrelin signalling over the past 25 years [1], no GHSR-targeted ther- apy has yet translated into clinical practice. The discovery of LEAP2 as an endogenous GHSR antagonist has reignited interest in this pathway as a therapeutic target for obesity and/or T2D [59, 139, 254, 259], but important mechanistic gaps remain. In particular, the physiological role of LEAP2 beyond GHSR antagonism, the tissue-specific actions of Page 15 of 24 47 ghrelin and desacyl-ghrelin, and the functional relevance of the ghrelin/LEAP2 ratio across different metabolic states require further clarification. Moreover, the redundancy and plasticity of central appetite-regulating circuits, together with the constitutive activity of GHSR and the development of tachyphylaxis, complicate pharmacological modulation of this system. Future research should focus on elucidating ghrelin- LEAP2 interactions to uncover previously unrecognized regulatory mechanisms and enable the development of novel therapeutic strategies. Rather than serving as a pri- mary driver of weight loss, modulation of ghrelin-LEAP2 axis may prove particularly valuable for improving meta- bolic resilience during energy deficit, preventing weight regain after weight reduction, and modulating reward-driven feeding. Continued integration of mechanistic, translational, and clinical research will be essential to determine whether targeting the ghrelin-LEAP2 system can complement cur- rent metabolic therapies and contribute to more effective strategies for the treatment of obesity and related metabolic derangements.

    The Ghrelin-LEAP2 System in Obesity and Diabetes: Pathophysiological Roles and Therapeutic Potential · 2026 · DOI

  • Triple receptor agonist retatrutide (GLP-1/GIP/glucagon receptor) demonstrates superior metabolic efficacy compared to dual agonists, but preclinical neuroprotective and anti-inflammatory effects remain preliminary and unvalidated in clinical populations. Studies must determine whether retatrutide modulates central inflammatory and neuroimmune pathways through GLP-1 and GIP receptor engagement in appetite-regulating brain regions.

    Metabolic inflammation at the adipose-brain axis · 2026 · DOI

  • The direct effects of lifestyle interventions and incretin-based therapies (GLP-1 receptor agonists, dual GLP-1/GIP agonists) on brain inflammation and blood-brain barrier integrity remain poorly characterized. Clinical validation studies are needed to determine whether these metabolic improvements translate to measurable reductions in central neuroinflammation and barrier dysfunction.

    Metabolic inflammation at the adipose-brain axis · 2026 · DOI

  • Cell-type-specific adipokine signaling pathways remain poorly defined, particularly for resistin receptor mechanisms in neurovascular and microglial inflammation. Identifying unresolved resistin receptors and their distinct signaling cascades across brain cell types is a key priority for understanding metabolic inflammation at the adipose-brain axis.

    Metabolic inflammation at the adipose-brain axis · 2026 · DOI

  • The meninges remain a largely unexplored site for sensing and integrating adipose-derived inflammatory signals during obesity. Focused investigation is needed to characterize how meningeal immune cells and structures detect and respond to adipokines, cytokines, and metabolic substrates from dysfunctional adipose tissue.

    Metabolic inflammation at the adipose-brain axis · 2026 · DOI

  • Despite a well-documented association between obesity and altered brain dopamine function, it remains elusive whether these alterations are (1) pre-existing, increasing the individual susceptibility to weight gain, (2) secondary to obesity, or (3) directly attributable to repeated exposure to western diet.

    Habitual daily intake of a sweet and fatty snack modulates reward processing in humans · 2023 · DOI

  • Despite different neuroendocrine measures having been associated with both gambling disorder (GD) and food addiction (FA), how appetite-regulating hormones may relate to the co-occurrence of both entities remain incompletely understood.

    Plasma concentration of leptin is related to food addiction in gambling disorder: Clinical and neuropsychological implications · 2023 · DOI

  • Many conflicting results have been obtained in the study of leptin (LEP) and leptin receptor (LEPR) gene variants that are associated with the obesity and diabetes possibly due to differences in the study populations.

    GHRL, LEP, LEPR genes polymorphism and their association with the metabolic syndrome in the Ukrainian population · 2023 · DOI

  • Even if many aspects remain to be explained, this finding suggests that ROHHADS could share similar pathogenetic mechanisms with other immune-mediated central nervous system disorders, and even more important, it might pave the way to a therapeutic chance for these patients by means of immunotherapy.

    Intrathecal Synthesis of Oligoclonal Bands in Rapid-Onset Obesity With Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation Syndrome · 2013 · DOI

  • Although the mechanisms behind this observation are not fully understood, identification of the main metabolic pathways affected by CR has generated interest in finding molecular targets that could be modulated by CR mimetics.

    Caloric restriction and chronic inflammatory diseases · 2011 · DOI

  • Rising childhood obesity and earlier onset of puberty suggest that modern, energy rich diets may distort these evolved energy allocation rules, but causal mechanisms remain unclear.

    Evolutionary trade-offs between growth and reproduction under obesogenic conditions: sex-biased skeletal and gonadal maturation in mice · 2026 · DOI

  • Birds maintain unusually high circulating glucose levels compared with other vertebrates without developing the diabetic complications observed in mammals, yet the mechanisms underlying this resistance remain unclear.

    Glucose and methylglyoxal alter plasma protein dynamics, immune traits and glucose homeostasis in a sex- and season-dependent manner in zebra finches · 2026 · DOI

  • However, the ability of endogenous compounds associated with obesity to prime human monocytes and thereby modulate subsequent response remains to be investigated.

    Priming of human monocytes by β-glucan and obesity-associated factors: modifications to global DNA methylation, gene expression, phenotype and function · 2026 · DOI

  • However, the role of GLP-1 signalling within the human NAc remains incompletely understood.

    Nucleus accumbens GLP-1 signaling and its role in reward and metabolic regulation: a systematic review · 2026 · DOI

  • Despite the small size of the MHb and its understudied status relative to the LHb (5, 7), its astrocyte population underwent clear morphological remodeling under all three conditions, with responses that differed not only between groups but also consistently between sexes.

    Astrocytic morphology in the Medial Habenula: sex differences and modulatory factors · 2026 · DOI

  • Animal models can provide insight into whether this differential prevalence is rooted in biological mechanisms, but prior studies have yielded conflicting findings.

    Vulnerability and Resilience to Activity-Based Anorexia is Not Sex-Dependent · 2026 · DOI

  • Introduction Despite its popularity and reported benefits in humans, preclinical characterization of the broader physiological impact of the 5:2 diet and potential mechanisms of action are lacking.

    The 5:2 diet induces male-specific weight loss and sex-independent enhancement of lipid storage in mice via activation of GHSR · 2026 · DOI

  • image Key points Vagal sensory nerves, which connect the gut and the brain, play a key role in regulating meal‐related physiology; however, their role in thermoregulation remains incompletely understood.

    Peripheral cholecystokinin promotes thermogenesis via vagal afferent signalling, hypothalamic oxytocin and sympathetic outflow to brown adipose tissue · 2026 · DOI

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48 open questions have been extracted from the limitations and future-work passages of 373 Regulation of Appetite and Obesity papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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