GLPs: What Every Researcher Should Know

Most conversations focus on one outcome: weight loss.

But there is much more for researchers to understand.

What happens to body composition when substantial weight is lost? Why can constipation become an issue? What do we know about hair loss? And what about less-discussed experiences involving motivation, pleasure and anhedonia?

Before looking at those questions, researchers first need to understand what these compounds actually are and clear up one of the biggest misconceptions surrounding the terms GLP-1, GLP-2 and “GLP-3.”

What Is GLP-1?

GLP-1 stands for glucagon-like peptide-1.

It is a naturally occurring hormone involved in several physiological processes, including glucose-dependent insulin secretion, glucagon signaling, appetite, satiety and gastrointestinal function.

Compounds such as semaglutide act at the GLP-1 receptor, which is why they are classified as GLP-1 receptor agonists.

Newer compounds, however, have expanded metabolic research beyond GLP-1 alone.

GLP-1 vs GLP-2 vs GLP-3: What Is the Difference?

One of the most common misconceptions online is that semaglutide is a “GLP-1,” tirzepatide is a “GLP-2,” and retatrutide is a “GLP-3.”

That is not scientifically accurate.

Is Tirzepatide a GLP-2?

No.

Tirzepatide is a dual GIP and GLP-1 receptor agonist.

Actual GLP-2, or glucagon-like peptide-2, is a separate naturally occurring intestinal hormone. It should not be confused with tirzepatide or interpreted as the second generation of a GLP-1 compound.

This distinction matters because receptor activity, rather than an informal GLP number, is what tells researchers how a compound works.

Is Retatrutide a GLP-3?

No.

Retatrutide is an investigational GIP, GLP-1 and glucagon receptor agonist.

The term “GLP-3” is sometimes used informally online because three receptors are involved, but there is not a corresponding GLP-3 hormone that accurately describes retatrutide.

A more useful way to understand these compounds is:

• Semaglutide: GLP-1 receptor agonism
• Tirzepatide: GIP + GLP-1 receptor agonism
• Retatrutide: GIP + GLP-1 + glucagon receptor agonism

That distinction is far more scientifically meaningful than simply labeling the compounds GLP-1, GLP-2 and GLP-3.

Weight Loss Does Not Tell the Entire Story

The substantial weight reductions observed in GLP-based research understandably receive enormous attention.

But researchers should ask another question:

What exactly is being lost?

Body weight includes fat, skeletal muscle and other lean tissues, water, glycogen and additional components.

That means a change on the scale is not automatically equivalent to a change in body fat.

GLPs and Lean Mass

Body-composition research involving semaglutide and tirzepatide has demonstrated reductions in fat mass alongside reductions in absolute lean mass.

In the SURMOUNT-1 DXA substudy involving tirzepatide, approximately three-quarters of the observed weight reduction was attributable to fat mass and roughly one-quarter to lean mass.

This does not mean these compounds simply “burn muscle.” Significant weight reduction through many methods can involve some decrease in lean tissue.

It does mean, however, that researchers should not evaluate outcomes using scale weight alone.

Body composition matters.

Researchers evaluating metabolic outcomes may also want to consider variables such as:

• Fat mass
• Lean mass
• Skeletal muscle
• Strength
• Physical function
• Protein intake
• Overall nutritional intake

GLPs and Constipation

Nausea may be the gastrointestinal effect most commonly associated with GLP-1 receptor agonists, but constipation deserves attention too.

GLP-1 signaling influences gastrointestinal function, and GLP-1 receptor agonists can affect gastric emptying.

At the same time, substantial appetite reduction may mean that less food, fiber and fluid are being consumed.

That combination can contribute to changes in bowel habits.

Researchers examining gastrointestinal effects should therefore consider more than nausea. Relevant observations may include:

• Constipation
• Diarrhea
• Nausea
• Vomiting
• Abdominal discomfort
• Dyspepsia
• Early satiety
• Changes in gastric emptying

Gastrointestinal response may also vary according to the compound being studied, dose, exposure and escalation schedule.

GLPs and Hair Loss: What Is the Connection?

Hair loss and hair shedding have become increasingly discussed alongside GLP-based weight reduction.

The important question is whether the compound itself is directly affecting hair follicles or whether physiological changes associated with substantial weight reduction may be contributing.

One possible explanation is telogen effluvium.

Telogen effluvium is a form of temporary excessive hair shedding that can occur after significant physiological stressors, including rapid or substantial weight loss.

Reduced food intake may also affect intake of protein and important micronutrients.

Researchers therefore need to distinguish between two very different statements:

Hair loss occurred while someone was using a GLP-based medication.

and

The GLP compound directly caused the hair loss.

Those statements are not scientifically interchangeable.

Researchers examining hair loss may want to consider:

• The rate of weight reduction
• Total caloric intake
• Protein intake
• Iron status
• Micronutrient intake
• Other physiological stressors
• The timing of hair shedding relative to weight loss

Appetite Suppression Can Have Downstream Effects

Reducing appetite is one thing.

Reducing nutritional intake too far is another.

When someone begins eating substantially less food, intake of more than just calories can decrease.

Potentially affected areas include:

• Protein
• Fiber
• Fluids
• Iron
• Vitamins
• Minerals
• Essential fatty acids

This creates an important research consideration.

Some experiences occurring alongside GLP-based treatment may involve downstream effects of major changes in appetite and dietary intake rather than one isolated receptor mechanism.

This distinction may be particularly relevant when researchers are evaluating fatigue, constipation, hair shedding or changes in body composition.

GLPs, Anhedonia and the Brain’s Reward System

One of the most interesting emerging areas of GLP research involves motivation, reward and anhedonia.

Anhedonia describes a reduced ability to experience pleasure or enjoyment from activities that would normally feel rewarding.

Some individuals have reported experiences such as:

• Reduced motivation
• Emotional flattening
• Less interest in previously enjoyable activities
• Changes in reward-seeking behavior

This area requires significant scientific caution.

Anhedonia has not been established as a common direct adverse effect of GLP-1 receptor agonists.

However, GLP-1 signaling extends beyond appetite and glucose regulation.

GLP-1 receptors and related pathways are also present within areas of the central nervous system involved in reward, motivation and reinforcement.

Researchers have consequently become interested in the relationship between GLP-1 signaling and reward-driven behaviors.

GLP-1-based therapies are also being studied in areas involving addictive and substance-related behaviors, making reward signaling an increasingly important area of investigation.

That raises an interesting research question:

If GLP signaling changes the reward associated with food, could reward processing involving other behaviors also change in some individuals?

Research has not yet provided a definitive answer.

Other possible contributors must also be considered, including:

• Significant caloric restriction
• Rapid weight reduction
• Fatigue
• Sleep disruption
• Nutritional deficiencies
• Other medications
• Pre-existing mental-health conditions
• Major lifestyle changes

Researchers should therefore avoid assuming direct causation.

However, changes involving motivation, pleasure or reward processing may still be important observations worthy of further investigation.

Persistent or significant mood changes, loss of pleasure, depression or suicidal thoughts should not simply be assumed to be a normal GLP-related effect and warrant evaluation by a qualified healthcare professional.

Retatrutide Research and Skin Sensitivity

Another less-discussed observation has emerged from research involving retatrutide.

Phase 2 obesity research reported cutaneous hyperesthesia and related skin-sensitivity experiences among some participants.

Hyperesthesia generally refers to increased sensitivity to sensory stimulation.

This is particularly interesting because skin sensitivity is not an effect most people would immediately associate with metabolic research.

Observations such as these demonstrate why researchers should examine the entire adverse-event profile rather than focusing exclusively on changes in body weight.

Retatrutide and Heart Rate

Retatrutide research has also observed dose-dependent increases in heart rate.

In phase 2 research, increases in heart rate peaked during treatment and subsequently declined.

Because retatrutide remains investigational, larger and longer-duration studies are important for understanding the significance of findings such as these.

More Receptors Do Not Automatically Mean Better

It can be tempting to look at metabolic research as a simple progression:

Single agonist → dual agonist → triple agonist

and assume that activating more receptors automatically means a compound is better or stronger.

That is not necessarily how the biology should be interpreted.

Different receptor combinations can create different physiological effects.

They may also create different tolerability and adverse-event profiles.

A triple-receptor agonist is therefore not simply a “stronger GLP-1.”

It represents a different combination of biological signaling pathways.

Instead of asking:

Which GLP is strongest?

Researchers should ask:

Which receptors does this compound activate, and what happens when those pathways are activated together?

What Should Every GLP Researcher Pay Attention To?

Perhaps the biggest takeaway is that GLP research should not revolve exclusively around the number on the scale.

Researchers should consider the broader physiological picture, including:

• Total body weight versus fat mass and lean mass
• Appetite versus actual nutritional intake
• Protein and micronutrient intake
• Constipation and gastrointestinal function
• Gastric emptying
• Hair shedding
• Changes in motivation and reward processing
• Unexpected sensory effects
• Heart-rate changes
• Differences between single-, dual- and triple-receptor agonism

Researchers also need to distinguish association from causation.

An event occurring during exposure to a compound does not automatically establish that the compound directly caused the event.

That distinction becomes especially important when substantial changes in body weight, diet, appetite and metabolism are happening simultaneously.

Frequently Asked Questions About GLPs

What does GLP-1 stand for?

GLP-1 stands for glucagon-like peptide-1. It is a naturally occurring hormone involved in glucose regulation, appetite, satiety and gastrointestinal signaling.

Is tirzepatide a GLP-2?

No. Tirzepatide is a dual GIP and GLP-1 receptor agonist. Actual GLP-2 is a different naturally occurring intestinal hormone.

Is retatrutide a GLP-3?

No. Retatrutide is an investigational triple GIP, GLP-1 and glucagon receptor agonist. The term “GLP-3” is informal internet terminology rather than a scientifically accurate classification.

Can GLP-based compounds cause constipation?

Constipation has been reported with GLP-1-based therapies. Gastrointestinal motility, changes in gastric emptying, reduced food intake, lower fiber intake and reduced fluid intake may all be relevant factors.

Can GLPs cause hair loss?

Hair shedding has been reported during substantial GLP-associated weight reduction. However, researchers must distinguish between direct drug effects and other contributors, including rapid weight loss, reduced calorie intake, inadequate protein or micronutrient intake, and telogen effluvium.

Can GLPs cause anhedonia?

Anhedonia has not been established as a common direct adverse effect of GLP-1 receptor agonists. However, GLP-1 signaling is being studied in brain pathways involving reward, motivation and reinforcement, making this an emerging area of research.

Does weight loss from GLPs include lean mass?

Body-composition research has shown that substantial weight reduction can involve decreases in both fat mass and lean mass. This is why researchers should consider body composition rather than relying exclusively on total scale weight.

The Bottom Line

GLP-based compounds have changed the direction of metabolic research, but some of the most interesting questions extend far beyond weight loss.

Understanding the difference between GLP-1 receptor agonism, dual GIP/GLP-1 receptor agonism and triple GIP/GLP-1/glucagon receptor agonism is an important starting point.

From there, researchers can look deeper.

What happens to fat and lean mass?

How does gastrointestinal function change?

Why might hair shedding occur?

How does substantial appetite reduction affect nutritional intake?

Could changes in reward signaling influence motivation or pleasure?

And what unexpected observations will emerge as newer multi-receptor compounds continue to be studied?

Those questions are where GLP research becomes considerably more interesting.