Roles of Gangliosides in Hypothalamic Control of Energy Balance: New Insights

Abstract

Gangliosides are essential components of cell membranes and are involved in a variety of physiological processes, including cell growth, differentiation, and receptor-mediated signal transduction. They regulate functions of proteins in membrane microdomains, notably receptor tyrosine kinases such as insulin receptor (InsR) and epidermal growth factor receptor (EGFR), through lateral association. Studies during the past two decades using knockout (KO) or pharmacologically inhibited cells, or KO mouse models for glucosylceramide synthase (GCS; Ugcg), GM3 synthase (GM3S; St3gal5), and GD3 synthase (GD3S; St8sia1) have revealed essential roles of gangliosides in hypothalamic control of energy balance. The a-series gangliosides GM1 and GD1a interact with leptin receptor (LepR) and promote LepR signaling through activation of the JAK2/STAT3 pathway. Studies of GM3S KO cells have shown that the extracellular signal-regulated kinase (ERK) pathway, downstream of the LepR signaling pathway, is also modulated by gangliosides. Recent studies have revealed crosstalk between the LepR signaling pathway and other receptor signaling pathways (e.g., InsR and EGFR pathways). Gangliosides thus have the ability to modulate the effects of leptin by regulating functions of such receptors, and by direct interaction with LepR to control signaling.

Chemoenzymatic Total Synthesis of GM3 Gangliosides Containing Different Sialic Acid Forms and Various Fatty Acyl Chains

“…The levels of human serum GM3 gangliosides containing various acyl chains have been shown to correlate with risk factors for metabolic diseases . Increased GM3 synthesis has been shown to associate with insulin resistance and impaired wound healing in patients with type 2 diabetes or in related mouse models. − GM3 has also been shown to inhibit the activities of receptor tyrosine kinases such as the epidermal growth factor receptor, − and such activity varies according to the sialic acid forms (Neu5Ac or Neu5Gc) . GM3 containing the Neu5Gc sialic acid form (Neu5Gc-GM3) has been found in different cancers, and Neu5Gc-GM3 extracted from horse erythrocytes has been used to form very-small-size-proteoliposomes with the Neisseria meningitidis outer membrane protein complex in clinical trials for breast cancer patients. − …”

Allosteric modulation of ghrelin receptor signaling by lipids

“…As a consequence, dysregulation in phosphatidylinositol synthesis, transport, or metabolism participates in human diseases involving membrane proteins misfunction 18 . Gangliosides are essential components of membrane microdomains that modulate the functioning of membrane proteins such as the insulin-or the epidermal growth factor receptor through a lateral association mechanism 19 . In addition, they have emerged as important regulators of metabolism, glucose homeostasis, and body weight 20 , all functions that are highly relevant to GHSR signaling.…”

Ganglioside GM3 Protects Against Abdominal Aortic Aneurysm by Suppressing Ferroptosis

“…26 Accordingly, GM3 has been shown to bind membrane receptors and to affect receptor signaling. 27,28 We speculated that the binding of GM3 to certain membrane proteins might affect intracellular iron content either directly or indirectly. To identify potential binding partners in HASMCs, we pulled down proteins bound to biotin-labeled GM3 using affinity streptavidin T1 beads and carried out proteomic analysis (Figure 4B and 4C).…”