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	Figure 1. Central regulation of glucose homeostasis is hypothesised to be mediated via interaction of pancreatic insulin and adipose tissue‐derived leptin in the central nervous system. Both hormones bind to their respective receptors, expressed in the hypothalamic arcuate nucleus and appear to interact via convergence of intracellular signaling at the IRS‐PI3K‐AKT pathway. Leptin sensitizes insulin signaling by activating IRS1, resulting in a modification of this molecule to a higher affinity to insulin signal transduction. This allows the transduction of the insulin signal into a glycemic response. Besides IRS1 also IRS2 and 4 are expressed in the hypothalamus but sensitization by leptin remains to be established. LepR: Leptin receptor; IR: insulin receptor; JAK: Janus kinase, IRS: Insulin receptor substrate, Pi3K: Phosphatidylinositol 3‐kinase.
	Figure 2. Model proposing that sensitization of insulin signaling in the hypothalamus is mediated via the WNT pathway. Leptin, similar to WNT 7a and 4 activates LRP‐6, resulting in inactivation of GSK3β (This inactivation can also be induced artificially by administration of a GSK3β inhibitor). Consequently, a positive feedback loop might be triggered in which the phosphorylation of inhibitory phosphorylation sites on IRS‐1 by GSK3β is reduced. This modification on IRS‐1 would result in activation of the IRS‐PI3K pathway by insulin, leading to an increase in phosphorylation of AKT. Phospho‐AKT, in turn, might enhance this mechanism by further inactivating GSK3β. Leptin induces activation of WNT target genes Axin‐2 and Cyclin‐D1, however, whether this increase is mediated by TCF7 and β‐Catenin and their respective role in central regulation of glucose homeostasis remains to be established (dotted arrows). LepR: Leptin receptor; IR: insulin receptor; JAK: Janus kinase, IRS: Insulin receptor substrate, Pi3K: Phosphatidylinositol 3‐kinase, TCF7: transcription factor 7.
	Figure 3. Gene‐therapeutic inhibition of the pro‐inflammatory IKKβ/NFκB pathway in neurons in the ARC by overexpressing a mutated form of IκBα (IκBα‐mt) in an AAV2 vector, partially protects from metabolic alterations induced by high fat diet. The expression of IκBα‐mt was under the control of the human synapsin‐1 promoter to restrict the expression to neurons and WPRE (Woodchuck hepatitis virus post‐transcriptional regulatory element) to ensure long‐term expression of the transgene. When animals overexpressing this mutated gene were fed a high‐fat diet they gained less fat mass, had reduced basal blood glucose levels, improved glucose tolerance and were more insulin sensitive than control mice. For details, see (29).
	Figure 4. Central and peripheral diet of glucose homeostasis associated with obesity and type two diabetes mellitus leads to cognitive impairment. In rodents on a high fat diet, the hypothalamus and the hippocampus appear to be particularly affected illustrated by the loss of central control of peripheral glucose homeostasis and energy balance, and memory deficits respectively. Mechanisms underlying these effects are the rapid development of insulin and leptin insensitivity, increased central levels of glucose resulting in glucotoxicity and the formation of advanced glycation end products (AGEs). Inflammation and lipotoxic fatty acid metabolites are also detected.
	Figure 5. Central regulation of glucose homeostasis is regulated by a coordinated action of nutrient absorption in the intestine and the crosstalk of leptin and insulin in the hypothalamus. Long chain saturated fatty acids, abundant in a Western diet, activate the the pro‐inflammatory IKKβ/NFκB pathway in neurons and microglia of the hypothalamus. This in turn disrupts the essential crosstalk of leptin and insulin signaling leading to an increase of centrally mediated hepatic glucose production and a reduction in insulin dependent glucose uptake in the muscle. Chronic consumption of a Western diet rich in long chain saturated fatty acids leads to an imbalance of glucose homeostasis and ultimately to the development of type 2 diabetes.

Teaching Material

Tups A, Benzler J, Sergi D, Ladyman SR, Williams LM. Central regulation of glucose homeostasis. Compr Physiol 2017, 7: 741-764. doi: 10.1002/cphy.c160015

Didactic Synopsis

Major Teaching Points:

• Peripherally produced metabolic hormones can act centrally to regulate whole body glucose homeostasis.
  • The satiety hormone leptin is able to centrally regulate glucose homeostasis at doses lower than that required to suppress food intake.
  • Insulin, produced by pancreatic beta-cells can act centrally to regulate glucose homeostasis, particularly through modulation of hepatic glucose production, as well as is well-known peripheral effects on glucose homeostasis.
• Obesity is associated with an inability of leptin and insulin to signal in the brain, termed leptin and insulin insensitivity, respectively. The central insensitivity to these two hormones contributes to dysregulation of glucose homeostasis. Central inflammation may underlie central insensitivity to leptin and insulin in obesity.
• Long-term dysregulation of glucose homeostasis resulting in high glucose levels and insulin resistance are contributing to impairments in memory and cognition.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: The peripherally produced hormones, leptin and insulin, can act in the brain, particularly the hypothalamus to regulate glucose homeostasis. These hormones bind to their receptors that are located on the cell membrane and this leads to the activation of intracellular signaling pathways that can then influence the activity of the cells leading to downstream effects such as regulating peripheral glucose levels. Leptin signaling can positively influence the ability of a cell to respond to insulin, called ‘sensitizing the cell to insulin signaling’, and this has been proposed to involve an intracellular signaling molecule called IRS1.

Figure 2. Teaching points: One intracellular signaling pathway that is proposed to play a role in leptin’s ability to sensitize cells to insulin signaling in the hypothalamus is called the WNT signaling pathway. GSK-3 β plays a key role in the WNT signaling pathway. Leptin has been found to reduce the activity of GSK-3β resulting in removal of inhibition of the molecule IRS1. Thus, insulin signaling via IRS1 can be increased, leading to increased pAKT and further downstream effects. The increase in pAKT can further suppress GSK-3β generating a positive feedback loop to further increase insulin signaling within the cell.

Figure 3. Teaching points: Inflammation in the hypothalamus may play a key role in insulin and leptin insensitivity in the hypothalamus in diet-induced obesity. Injecting a specially made virus, which is designed to decreases inflammation in the arcuate nucleus, a key site of insulin and leptin action in the hypothalamus, can prevent mice from some of the effects of eating a high fat diet. When these virus-treated mice eat a high fat diet they have better regulation of blood glucose levels and are not as fat as mice that eat a high fat diet and did not get treated with this virus.

Figure 4. Teaching points: Dysfunction of glucose homeostasis in the body can lead to impaired memory and cognition. The proposed causes of which include exposure to constant high levels of glucose, insulin, and leptin insensitivity, and toxicity due to increased levels of long-chain saturated fatty acid metabolites.

Figure 5. Teaching points: Leptin and insulin can act in the hypothalamus to centrally regulate glucose homeostasis. Long chain saturated fatty acids, abundant in a Western diet, activate the proinflammatory IKKβ/NFκB pathway in cells of the hypothalamus. Activation of this pathway can disrupt the interaction of leptin and insulin intracellular signaling and therefore impair the normal regulation of glucose homeostasis by these two hormones and this can contribute to the development of type 2 diabetes.