When it comes to type 2 diabetes, we tend to think we know all there is to know and are resigned to lifelong insulin injections. But its causes are not uniform throughout the world. For instance, in Asians a decrease in insulin production by pancreatic islet cells is central, while in Europeans the impaired ability of circulating insulin to regulate glucose levels is critical in the development of type 2 diabetes.

Leptin, a hormone produced by fat cells crosses the blood-brain barrier to mobilize brain regulatory circuits that determine the intricate metabolic balance of food intake, the use of nutrients to generate energy, and the storage of nutrients for future needs.

A new study shows the brain’s ability to perceive leptin plays a central role in type 2 diabetes and offers a key therapeutic target.

Researchers led by Vincent Prévot, PhD, research director at Inserm, head of the laboratory of development and plasticity of the neuroendocrine brain in Lille, France, had shown in earlier studies that special cells called tanycytes with processes that elongate deep into the hypothalamus of the brain, shuttle leptin into the brain to reach target neurons by attaching to surface receptors (LepR).

Vincent Prévot, PhD, research director at Inserm, head of the laboratory of development and plasticity of the neuroendocrine brain in Lille, France, is senior author on the study.

The group’s earlier findings were questioned by researchers who could not detect LepR in tanycytes. In the current study, the authors established the expression of functional LepR in tanycytes using multiple models. They showed tanycytes respond to leptin by triggering calcium waves and downstream phosphorylation of target proteins, and identified a protein complex called LepR–EGFR, that transports leptin across these cells.

The authors noted, “The assumption that LepR is not expressed in tanycytes could be due to the fact that, like astrocytes, these specialized hypothalamic glia [tanycytes] do not express commonly used Cre-dependent reporter genes or that most alternative detection techniques used to date are insufficiently sensitive.”

The authors showed the lack of LepR in tanycytes blocks leptin entry into the brain, inducing an increase in food intake and fat synthesis (lipogenesis), and a decrease in insulin secretion by pancreatic β-cells that results in glucose intolerance.

The findings are reported in the article, “Leptin brain entry via a tanycytic LepR–EGFR shuttle controls lipid metabolism and pancreas function,” which was published in the journal Nature Metabolism. This new leptin transport mechanism could be crucial to the pathophysiology of diabetes and obesity and opens doors for new strategies for therapeutic interventions.

Previous research has revealed that leptin transport is impaired in subjects who are obese or overweight explaining their inability to regulate their appetite.

“We show that the brain’s perception of leptin is essential for the management of energy homeostasis and blood sugar. We also show that blocking the transport of leptin to the brain impairs the functioning of the neurons that control pancreatic insulin secretion,”  says Prévot.

Three months after the researchers deleted the LepR receptor located on the surface of the tanycytes in experimental mouse models, the mice showed a marked increase in their fat mass (which doubled over the period) as well as a loss of muscle mass (which was reduced by more than half). The mice also experienced moderate weight gain.

The scientists regularly measured blood sugar levels following the injection of glucose in these LepR lacking mice. They found that to maintain normal blood sugar levels the mice secreted more insulin during the first four weeks of the experiment and by the end of three months following the removal of the LepR receptor, the ability of the pancreas to secrete insulin was exhausted.

The absence of LepR receptors impaired leptin transport to the mouse brain resulting in a pre-diabetic state when the body releases more insulin than usual to retain normal blood sugar levels. In the long term, the mice were unable to secrete excess insulin and could no longer control their blood sugar levels. The study suggests impaired leptin transport to the brain plays a role in the development of type 2 diabetes.

To rescue type 2 diabetes and to establish its underlying cause in LepR deficient mice, the scientists reintroduced leptin to the brain and observed the immediate restoration of the ability of the pancreas to secrete adequate levels of insulin and normal blood sugar levels. The mice regained a healthy metabolism. This study establishes the brain’s role in type 2 diabetes, directing further research into a disease that until now has not been considered a disease of the central nervous system.

Could treatments that increase leptin transport in the brain in prediabetics offer an alternative to insulin injections in patients with type 2 diabetes? “It would be exactly the point, indeed,” says Prévot, “because, increased leptin transport in the brain would boost the function of the pancreas and thus prevent insulin insufficiency.”