Many mechanisms can contribute to complex diseases such as metabolic diseases; thus, combination therapies may be required to target individual underlying pathological mechanisms. A new study combines glucagon-like peptide-1 (GLP1) and estrogen in a single molecule, allowing selective targeting of this conjugate to cells that express the GLP1 receptor. This strategy improves the metabolic profile of obese mice without the adverse side effects associated with estrogen therapy (pages 1847–1856).
Human longevity has dramatically increased in the last century as a result of major technological and therapeutic advances in health care. In the last decades, however, the spread of chronic metabolic disorders (such as obesity, type 2 diabetes and cardiovascular diseases) threatens to decrease healthy lifespan. Whereas the incidence of such disorders keeps increasing, the development of new therapies faces a period of stagnation. In this issue of Nature Medicine, Finan et al.1 describe an ingenious method to couple two different therapeutic molecules, and show that such an approach could perhaps be used to treat metabolic disorders, thus opening up new avenues for drug discovery.
Metabolic syndrome is a substantial health issue in modern societies and affects a large percentage of the population in Western societies. Obesity is a major factor that leads to other metabolic disturbances and heart disease. Despite accumulating knowledge on the pathways and circuitries involved in the regulation of energy balance over recent decades, treatments for obesity have been elusive2. In 1994, leptin was discovered3 and was shown to be a potent anorexigenic hormone4 that acts in the brain to decrease food intake5. Another endogenous hormone capable of reducing appetite is estrogen, which was described to function in the brain in a way similar to leptin6. Despite the ability of estrogen treatment to reduce body weight and appetite, its clinical use is limited due to the severity of its side effects, as highlighted by an increased incidence of cancer after estrogen treatment. In their recent study, Finan et al.1 set out to target the action of hormones such as estrogen on specific cellular populations with the aim of avoiding the off-target side effects associated with such therapies (Fig. 1).
GLP1 is among a number of hormones that have recently been found to play a part in regulating metabolism5. It is produced mainly in the gut in response to intestinal nutrients, potently enhances glucose-dependent insulin secretion in the pancreas and also has anorexigenic effects by acting in the hypothalamus and brainstem7(Fig. 1). GLP1 analogs are approved as antidiabetic agents in the treatment of type 2 diabetes, as are inhibitors of the enzyme that degrades GLP1 (dipeptidyl peptidase-4). Finan et al.1 conjugated estrogen to GLP1 to form a stable GLP1–estrogen molecule that could bind GLP1 receptors specifically in the cells that express this receptor, allowing the uptake of the stable complex into these cells and the signaling of estrogen to intracellular nuclear receptors. The authors thus combined the specificity of the metabolic actions of GLP1 with the strong effects of estrogen as a leptin mimetic.
By rigorously testing different combinations of conjugated molecules, the authors showed that GLP1–estrogen improved the metabolic profile of insulin-resistant diet-induced obese mice by acting as a potent anorexigenic molecule in the brain. They found that the anorexigenic effects of GLP1–estrogen were abrogated in mice lacking the GLP1 receptor in their brain, highlighting the importance of brain circuitries8 in mediating the effects of the conjugate. Notably, the anorexigenic effects of estrogen in animal models of metabolic disease are strongly linked to the hypothalamic pro-opiomelanocortin (POMC) neurons in the arcuate nucleus8. Estrogen induces rapid synaptic plasticity in the arcuate nucleus8, an effect similar to those of leptin9. Finan et al.1 suggest that the anorexigenic effect of GLP1–estrogen is mediated by similar circuitry, on the basis of the changes in the arcuate nucleus gene expression profile that they observed after mice were administered the conjugate.
Notably, the authors found that treatment of mice with the GLP1–estrogen conjugate was not associated with the side effects seen with estrogen therapy alone, such as effects on reproductive tissues and oncogenicity (Fig. 1). However, it is important to consider that GLP1 receptors are broadly expressed in the body and are not specific to the neuronal populations that regulate metabolism. Pancreatic beta cells, for example, also express this receptor, and the long-term effects of combination molecules such as GLP1–estrogen on nontarget cells will deserve careful further studies. In addition, even drugs targeted to act specifically in the neurons that regulate metabolism in the arcuate nucleus might still lead to undesirable long-term side effects2. The dogma that hypothalamic neurons have specific identities and functions has already been challenged2,10, and it is evident that homeostatic circuitries in the brain are highly connected and that their interactions determine whole-body homeostasis. Neuronal populations that are clearly connected to energy balance are also involved in other non–metabolism-related behaviors10, emphasizing the complexity of such systems.
The combination of multiple hormones in a single stable molecule as shown by Finan et al.1 holds promise for drug design. Rapid advances in the identification of the gene expression profiles of specific cellular populations, together with the already available large library of compounds could, potentially, lead to a multitude of new therapeutic formulations. The activation or deactivation of specific cellular pathways might lead to important new therapeutic innovations to improve human health. It is important to note, however, that most of the data available on the circuitries and gene expression in different cell populations are based on animal work. Therefore, the validation of such data sets in human tissues will be an important step to allow the effective formulation of such combination therapies.
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Dietrich, M., Horvath, T. A marriage made to last in drug design. Nat Med 18, 1737–1738 (2012). https://doi.org/10.1038/nm.3018
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DOI: https://doi.org/10.1038/nm.3018