An important paper from Dr. Francesca Galbiati on hypothalamic obesity

HYPOTHALAMIC OBESITY: HOW TO HELP THE FIGHT AGAINST HUNGER-PROMOTING, EVOLUTIONARILY CONSERVED BRAIN NETWORKS

From Francesca Galbiati, MD, neuroendocrinologist and neuroscientist,  Assistant Professor  medicine UCSF, and PWN contributing author – Tumors, surgery, traumatic brain injury, and more may severely damage the hypothalamus^1,2. The hypothalamus is the master coordinator of brain neuroendocrine signaling (as it directly superintends the pituitary gland)^3–5. It is also a central node of the salience network, a large-scale brain network that coordinates the amygdala, insula, brainstem, and orbitofrontal cortex to integrate stimuli from the environment and the body to generate behaviors⁶. Behaviors under the hypothalamic control include, but are not limited to, eating behavior (in response to both satiety and social cues), social interactions, and reward responses (including hedonic eating)^7–10. It is then intuitive that if the hypothalamus is damaged, its hormone signals will be disrupted, and its brain circuit connections will malfunction.

A key hypothalamic receptor implicated in satiety signaling is the melanocortin-4 receptor (MC4r)¹¹. The MC4r is activated by proopiomelanocortin (POMC) neurons (anti-hunger or anorexigenic) and inhibited by Agouti-related peptide (AgRP)/Neuropeptide Y (NPY) neurons (pro-hunger or orexigenic)^11,12. Genetically determined defects in the MC4r pathway cause severe obesity and hyperphagia (insatiable hunger), presenting in childhood¹¹.

We have both pro- and anti-hunger signals in the brain – why then, when the hypothalamus is damaged, do the pro-hunger signals prevail? Well, evolution may give us the answer. In human history, access to and abundance of food are relatively recent. Our bodies have adapted over millions of years to conserve energy and survive during times of food scarcity. The stronger effect of AgRP/NPY neurons on feeding behavior than POMC neurons has been, in fact, demonstrated in several studies^12–14. This orexigenic (pro-hunger) predominance is what needs to be hit in hypothalamic obesity. It is then clear how treating this disorder is extremely challenging.

An opposite phenotype to hypothalamic obesity has been rarely described in children with a tumor involving the hypothalamus. These kids present severe weight loss and undernutrition, which could eventually be fatal¹⁵. This syndrome is called Diencephalic Syndrome as it involves the brain structures in the diencephalon, including the thalamus, subthalamus, hypothalamus, and epithalamus.  While the brain networks involved in diencephalic syndrome are unknown, increased action of POMC-like peptides (like β-lipotropin) has been hypothesized¹⁶. This syndrome is significantly rarer than hypothalamic obesity, suggesting how evolutionary pro-hunger predominance often prevails.

The POMC-AgRP/NPY system is modulated by several other peptides, which maintain a constant balance between pro- and anti-hunger signals by activating and inhibiting the circuits. They include, but are not limited to the following (also see Figure 1):

• Glucagon-like peptide 1 (GLP1) is a primarily gut-derived hormone that acts in the brain to enhance POMC neurons and inhibit AgRP/ NPY neurons, so favoring weight loss and decreased hunger¹².
• Oxytocin is a primarily hypothalamic neurohormone that decreases food intake and increases energy expenditure, and its action is enhanced by POMC neurons and inhibited by AgRP/ NPY neurons¹⁷.
• Ghrelin is the primary stimulator of the AgRP/ NPY circuit¹².
• Leptin is a strong inhibitor of the AgRP/ NPY circuit and an activator of the POMC circuit¹².

It is intuitive how these peptides may offer therapeutic targets for hypothalamic obesity.

A promising treatment strategy that has led to successful “primary” (meaning, not hypothalamic or genetic in origin) treatment are GLP1 receptor agonists (GLP1-RA). These medications have become very popular in the last decade and allow to achieve weight loss that is comparable to bariatric surgery. Just a few studies are available in hypothalamic obesity; however, they showed promising results, as did my hands-on patient experience^18,19. Despite the obvious need for treatment and higher cumulative cardiovascular risk for patients with hypothalamic obesity (as the onset is often at a young age), insurance coverage is often challenging and frequently denied. GLP1-RA’s may also help with other hypothalamic-related complications such as central sleep apneas.

MC4r agonists have also been studied (and, in specific cases, approved) for genetic obesity, but not yet for acquired hypothalamic obesity. Setmelanotide is one example^,20, and the great news for our patients is that this medication was just approved last week for the treatment of non-genetic hypothalamic obesity!²¹ I look forward to being able to use this medication for our patients.

Oxytocin is available as an intranasal spray, though it is not yet FDA-approved for use²². A study of carbetocin (a longer-acting oxytocin analogue) showed clinically meaningful improvements in self-reported hyperphagia and anxiety symptoms in Prader-Willi syndrome (a genetic condition where hypothalamic and oxytocinergic pathways are disrupted)²³. Intranasal oxytocin did not show weight loss but showed improved impulse control and anxiety vs. placebo in kids with hypothalamic obesity²⁴. Still, optimal dosages and frequency of intranasal oxytocin have not yet been established, and further and larger studies are needed. It is important to be aware that, not being FDA-approved, when providers seek oxytocin prescription in a compounding pharmacy, it is extremely important to ensure the pharmacy quality standards (e.g. stability, potency, purity tests), otherwise risks for patients may be significant.

In conclusion, hypothalamic obesity is one of the most complex hypothalamic complications pituitary endocrinologists face. Besides increased cardiovascular risk and increased mortality, hypothalamic obesity becomes a family’s disease. Patients have little control over it, and the caregivers’ burden may become unendurable. Urgent treatment options, approvals, and drug development are needed.

Scheme illustrating how peripheral hormones and gut–brain signals modulate hypothalamic circuits to regulate feeding behavior and energy expenditure. In the arcuate nucleus (ARC), leptin (from adipose tissue) promotes satiety by activating anorexigenic POMC/CART neurons and inhibiting orexigenic AgRP/NPY neurons, whereas ghrelin(from the stomach) activates AgRP/NPY neurons to increase feeding drive. GLP‑1 signaling (originating from the gut and brainstem nucleus tractus solitarius, NTS) is shown as a net satiety-promoting input acting on hypothalamic targets including the ARC and GLP‑1 receptor (GLP‑1R)–expressing pathways. POMC neurons release melanocortin peptides (e.g., α‑MSH) that activate MC4R-expressing neurons in the paraventricular nucleus (PVN), while AgRP functions as a physiological antagonist/inhibitory signal on MC4R pathways. Downstream PVN MC4R neurons and oxytocin neurons promote satiety-associated outputs, resulting in reduced food intake and increased energy expenditure, whereas AgRP/NPY activity increases feeding drive. Blue arrows indicate activation and red blunt arrows indicate inhibition; dashed outlines denote hypothalamic subregions. This diagram represents simplified, net directional effects and does not depict all parallel brainstem, limbic, autonomic, or endocrine pathways.

Abbreviations: ARC, arcuate nucleus; PVN, paraventricular nucleus; POMC, pro-opiomelanocortin; CART, cocaine- and amphetamine-regulated transcript; AgRP, agouti-related peptide; NPY, neuropeptide Y; MC4R, melanocortin-4 receptor; GLP‑1, glucagon-like peptide‑1; GLP‑1R, GLP‑1 receptor; NTS, nucleus tractus solitarius; α‑MSH, alpha–melanocyte-stimulating hormone.

 

References

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Image by Christine Sponchia from Pixabay

 

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