The carnitine palmitoyltransferases (CPTs) play a key role in controlling the oxidation of long-chain fatty acids and are potential therapeutic targets for diseases with a strong metabolic component, such as obesity, diabetes, and cancer. Four distinct proteins are CPT1A, CPT1B, CPT1C, and CPT2, differing in tissue expression and catalytic activity. CPT1s are finely regulated by malonyl-CoA, a metabolite whose intracellular levels reflect the cell's nutritional state. Although CPT1C does not exhibit significant catalytic activity, it is capable of modulating the functioning of other neuronal proteins. Structurally, all CPTs share a Y-shaped catalytic tunnel that allows the entry of 2 substrates and accommodation of the acyl group in a hydrophobic pocket. Several molecules targeting these enzymes have been described, some showing potential in normalizing blood glucose levels in diabetic patients, and others that, through a central mechanism, are anorexigenic and enhance energy expenditure. However, given the critical roles that CPTs play in certain tissues, such as the heart, liver, and brain, it is essential to fully understand the differences between the various isoforms. We analyze in detail the structure of these proteins, their cellular and physiological functions, and their potential as therapeutic targets in diseases such as obesity, diabetes, and cancer. We also describe drugs identified to date as having inhibitory or activating capabilities for these proteins. This knowledge will support the design of new drugs specific to each isoform, and the development of nanomedicines that can selectively target particular tissues or cells. SIGNIFICANCE STATEMENT: Carnitine palmitoyltransferase (CPT) proteins, as gatekeepers of fatty acid oxidation, have great potential as pharmacological targets to treat metabolic diseases like obesity, diabetes, and cancer. In recent years, significant progress has been made in understanding the 3-dimensional structure of CPTs and their pathophysiological functions. A deeper understanding of the differences between the various CPT family members will enable the design of selective drugs and therapeutic approaches with fewer side effects.

Medical treatments of neuron-related disorders are limited due to the difficulty of targeting brain cells. Major drawbacks are the presence of the blood–brain barrier and the lack of specificity of...

Carnitine palmitoyltransferase 1A (CPT1A) is a central player in lipid metabolism, catalyzing the first step to fatty acid oxidation (FAO). Inhibiting CPT1A, especially in the brain, can have several pharmacological benefits, such as in treating obesity and brain cancer. C75-CoA is a strong competitive inhibitor of CPT1A. However, due to its negatively charged nature, it has low cellular permeability. Herein, we report the use of poly-ion complex (PIC) micelles to deliver the specific CPT1A inhibitors (±)-, (+)-, and (–)-C75-CoA into U87MG glioma cells and GT1-7 neurons. PIC micelles were formed through charge-neutralization of the cargo with the cationic side chain of PEG-poly{N-[N′-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-PAsp(DET)), forming particles with 55 to 65 nm diameter. Upon short-term incubation with cells, the micelle-encapsulated CPT1A inhibitors resulted in up to 5-fold reduction of ATP synthesis compared to the free drug, without an apparent decline in cell viability. Micelle treatment showed a discernible decrease in ¹⁴C-palmitate oxidation into CO₂ and acid-soluble metabolites, confirming that the substantial lowering of ATP production has resulted from FAO inhibition. Micelle treatment also diminished IC₅₀ by 2 to 4-fold over the free drug-treated U87MG after long-term incubation. To measure the cellular uptake of these CoA-adduct loaded PIC micelles, we synthesized a fluorescent CoA derivative and prepared Fluor-CoA micelles which showed efficient internalization in the cell lines, both in 2D and 3D culture models, especially in neurons where uptake reached up to 3-fold over the free dye. Our results starkly demonstrate that the PIC micelles are a promising delivery platform for anionic inhibitors of CPT1A in glioma cells and neurons, laying the groundwork for future research or clinical applications.

Targeting brain lipid metabolism is a promising strategy to regulate the energy balance and fight metabolic diseases such as obesity. The development of stable platforms for selective delivery of drugs, particularly to the hypothalamus, is a challenge but a possible solution for these metabolic diseases. Attenuating fatty acid oxidation in the hypothalamus via CPT1A inhibition leads to satiety, but this target is difficult to reach in vivo with the current drugs. We propose using an advanced crosslinked polymeric micelle-type nanomedicine that can stably load the CPT1A inhibitor C75-CoA for in vivo control of the energy balance. Central administration of the nanomedicine induced a rapid attenuation of food intake and body weight in mice via regulation of appetite-related neuropeptides and neuronal activation of specific hypothalamic regions driving changes in the liver and adipose tissue. This nanomedicine targeting brain lipid metabolism was successful in the modulation of food intake and peripheral metabolism in mice.

Nose-to-brain delivery is advancing with mucoadhesive and mucopenetrative nanomedicines, enabling effective intranasal transport of therapeutics like oxytocin and insulin through optimized formulations and predictive in vitro – in vivo models.