Organism Metabolism & Homeostasis

Adipose tissue functions as the body’s primary reservoir of stored energy. Under conditions of excess food, fat cells, known as adipocytes, convert energy in the form of glucose and fatty acids into triglycerides, which it stores for future energy needs. In periods of low energy, triglycerides are then broken down and released to fill the deficit.

However, adipocytes are not just passive reservoirs of stored energy that respond to energy needs. As one of the sites involved in a complex web of interactions between signaling networks including apelin, peroxisome proliferator-activated receptor (PPARs), retinoic X receptors (RXRs), insulin and others, adipocytes play an important role in regulating energy metabolism and energy homeostasis. A critical part of its ability to preserve metabolic health is attributed to adipose tissue’s metabolic, structural and phenotypic plasticity (1).

Adipogenesis pathway

Adipocytes are derived from mesenchymal stem cells, differentiating from preadipocytes into adipocytes in response to hormonal signals and cytokines that coordinate the activity of CCAAT-enhancer-binding proteins (C/EBPs) and PPARγ transcription factors that in turn regulate expression of genes required for adipocyte formation (2).

There are three main types of adipocytes: white, brown and brite (also known as beige). Collectively, they are the primary site of energy storge for the body. In addition to storing fat, adipocytes produce adipokines or adipocytokines that play a role in metabolism and energy homeostasis as well as broader roles in immunity and neuroendocrine function. Apelin is one of those adipokines, playing a role in a variety of physiological processes including regulation of glucose and lipid metabolism.

Apelin signaling pathways

Apelin is synthesized as a pre-pro-peptide that is cleaved to generate multiple active forms. These isoforms possess similar functions but display different tissue distribution, potency and receptor binding affinity. Apelin acts as a ligand for the APJ receptor (angiotensin II receptor like-1, AT-1), a G-protein coupled receptor.

In adipocytes and skeletal muscle, apelin stimulates glucose uptake, in part by increased insulin sensitivity (see insulin signaling below for details) (3). It also has a negative effect on lipolysis, reducing fatty acid generation and release. In the pancreas, apelin inhibits insulin secretion through AMPK activation and cAMP downregulation while in the liver, apelin has anti-insulin resistance properties.

PPAR signaling

PPAR and its partner RXR are additional influencers of the careful balance of metabolism and energy homeostasis.

The peroxisome proliferator-activated receptor (PPAR) family of ligand-activated transcriptional regulators consists of PPARα, PPARδ and PPARγ. Activated by ligands including n-3 and n-6 unsaturated fatty acids and their eicosanoid products, PPARs are closely linked to intracellular lipid levels and often regulate the expression of genes involved in lipid metabolism (4).

During periods of fasting and increased energy need, the PPAR family of transcription factors (see above) is activated, dimerizing with RXRα to influence lipid and glucose metabolism. The different PPARs have distinct physiological roles stemming from differing expression patterns. PPARα is highly expressed in liver, heart and kidney cells. PPARδ, also expressed in liver and heart, is additionally expressed in pancreatic islet cells, skeletal muscle, skin, immune cells and adipocytes. More ubiquitously expressed, PPARγ plays a role in many additional processes beyond lipid and glucose metabolism including adipogenesis (see above).

RXRα signaling

For its part, RXRα is a member of the retinoic X receptor (RXR) family of transcription factors, which, like retinoic acid receptors (RARs), are activated by binding of non-steroid hormone retinoids including vitamin A and its derivatives. When activated, RXR/RAR heterodimers undergo conformational changes that result in the release of corepressors and binding of coactivators, enabling regulation of target genes via retinoic acid response element (RARE) binding sites.

A few other RXRα dimerization partners regulate metabolism and energy homeostasis, either directly or through cross talk with PPARα or other signaling pathways. Beyond PPARs, these RXRα partners and their effects include:

• FXR/RXRα – Farnesoid X receptor (FXR) is primarily expressed in the intestine and liver. When activated by rising bile acid levels, FXR dimerizes with RXR activating expression of genes that inhibit bile synthesis. In addition to negatively regulating bile production, FXR positively regulates fatty acid and triglyceride synthesis as well as gluconeogenesis (5), with PPAR cross talk noted (6).
• LXR/RXRα – Expressed at high levels in both liver and adipose tissue, liver X receptors (LXRs) are involved in fatty acid and cholesterol metabolism. Additional roles have been noted in control of glucose metabolism with LXR shutting down gluconeogenesis in liver cells while promoting glucose uptake in adipose cells, in this case by upregulating expression of GLUT4, an insulin-sensitive glucose transporter (7).
• PXR/RXRα – Pregnane X receptor (PXR) is often studied for its central role in exogenous drug metabolism and excretion through upregulation of cytochrome P450 enzymes and drug efflux pumps. However, it also plays a role in endogenous metabolism, downregulating both gluconeogenesis and glucose uptake in liver cells and upregulating fatty acid oxidation (8).
• TR/RXRα – Similar to LXR, thyroid receptor (TR) downregulates gluconeogenesis in hepatocytes, in this case through modulating insulin sensitivity (9). It also plays a role in upregulating fatty acid oxidation.
• VDR/RXRα – Often studied for its role in calcium-phosphate homeostasis, vitamin D receptor (VDR) is another RXR partner that influences fatty acid oxidation, in this case negatively regulating it and instead promoting lipid storage (10).

Insulin receptor signaling

As suggested above by multiple references to insulin as a point of indirect regulation or cross talk, insulin is a central figure in metabolism and energy homeostasis. It suppresses gluconeogenesis in the liver while stimulating glucose uptake as well as lipogenesis and storage in muscle and fat cells (11). Insulin mediates its metabolic effects through a tyrosine kinase receptor (insulin receptor or INSR), adaptor proteins and ultimately serine-threonine kinases, including GSK3, AKT and PKA.

Other influences on metabolism and energy homeostasis

Fat tissue, and by extension metabolism and energy homeostasis, influences, and is influenced by, multiple other signaling pathways and physiological processes. Alpha adrenergic signaling inhibits breakdown of fat. Inflammation affects lipid metabolism leading to an increase in serum triglycerides. Disrupting circadian rhythms impacts glucose and lipid metabolism.

Maintaining energy homeostasis requires a careful balance of many factors. Obesity, one visible result of energy intake exceeding energy output, is linked to many conditions including iron deficiency, diabetes, heart disease and cancer. In part through dysregulation of metabolism and energy homeostasis, but also through less expected mechanisms such as increased inflammation. Understanding how these signaling pathways interact and their points of regulation can provide insights into potential therapeutic targets for managing metabolic diseases, obesity and its comorbidities.

References

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