The Problem with GLP-1s

GLP-1 agonists work — millions of people are losing weight on semaglutide, tirzepatide, and their successors. The appetite suppression is real; the caloric deficit follows. But something is wrong with the outcomes.

People are lighter but weaker. Thinner but exhausted. 'Ozempic Face' has become a troubling phenomenon. The scale moves, but energy doesn't follow. In clinical trials, 30–40% of weight lost on GLP-1 therapy is lean tissue—not fat. For someone losing fifty pounds, that's fifteen to twenty pounds of muscle gone. This is not a side effect. It is a predictable — and concerning — consequence of how these drugs work.

GLP-1 agonists create deficits by suppressing appetite. But a deficit is pressure, not direction. Without signals telling the body what to burn, it burns both fat and muscle. The body doesn't preferentially protect lean tissue just because you'd like it to.

Semaglutide and tirzepatide suppress glucagon secretion as part of their glycemic control mechanism. Glucagon does more than regulate blood sugar—when glucagon is suppressed, the liver's capacity to burn fat is constrained. You're eating less and oxidizing less efficiently. The result is the metabolic flatness GLP-1 users describe: weight loss without energy, deficit without combustion.

Weight loss requires two axes working together. The first axis is central—appetite, intake behavior, the decision to eat. GLP-1s address this effectively. The second axis is peripheral—oxidation machinery, mitochondrial capacity, the ability to actually burn what's been mobilized. GLP-1s ignore this axis — semaglutide and tirzepatide actively impair it.

This is why GLP-1 monotherapy produces weight loss but not recomposition. The deficit exists; the direction doesn't. Fat and muscle leave together because nothing told the body to prefer one over the other.

Retatrutide: The Metabolic Foundation

Retatrutide is a different molecule. It activates three receptors: GLP-1, GIP, and glucagon. The first two provide appetite suppression and glycemic smoothing. The third—glucagon—is what separates retatrutide from its predecessors.

Glucagon receptor activation preserves the liver's fat oxidation. Resting energy expenditure rises rather than falls. Fat is mobilized and burned, not just stored less. This is why retatrutide users often report better energy and less of the "flatness" that characterizes typical GLP-1 therapy.

At the high doses used in obesity trials (8–12 mg weekly), retatrutide behaves as a bariatric drug—dramatic weight loss, strong appetite suppression, significant reduction in energy intake. But the dual-axis approach uses retatrutide differently: as a low-dose metabolic stabilizer, typically 1–4 mg weekly.

At these doses, the intent is not simply maximal weight loss. It is metabolic reprogramming. While appetite becomes quieter and more predictable, glucose curves flatten, insulin sensitivity improves—without collapsing oxidative capacity. This is the foundation. Everything that follows assumes it is in place. But retatrutide alone is still incomplete. It preserves the peripheral axis; it does not build it.

NAD⁺

Before the oxidation machinery can run, it needs fuel. NAD⁺ is that fuel.

Nicotinamide adenine dinucleotide is required at every step of fat burning. Beta-oxidation—the breakdown of fatty acids inside mitochondria—consumes NAD⁺ at each cycle. The electron transport chain uses NAD⁺ as its primary electron carrier. Sirtuins, which regulate downstream gene expression and coordinate stress responses, require NAD⁺ to function.

When retatrutide and exercise increase oxidative demand, NAD⁺ consumption rises. If NAD⁺ pools are depleted—and they typically are with age, chronic inflammation, or metabolic dysfunction—the system cannot execute. Fat is mobilized but not burned. The signal arrives at machinery that lacks the capacity to respond. This manifests as fatigue, incomplete oxidation, and the familiar sensation of being "wired but underpowered."

Capacity Layer for GLP-1s

This is why NAD⁺ is treated as the first layer—without adequate NAD⁺, the subsequent interventions have nothing to work with. You can mobilize fat and tell mitochondria to burn it, but if the cofactor capacity isn't there, nothing happens.

NAD⁺ is also the most accessible entry point. For those already on GLP-1 therapy who aren't ready for a multi-peptide stack, adding NAD⁺ alone addresses the most immediate constraint: the oxidative machinery has the capacity to run.

This single addition can shift the experience from "eating less but feeling depleted" to "eating less and actually burning." It is not the complete solution—the subsequent layers add transport, programming, and protection—but it is the foundation that makes those layers possible.

Oral vs. Injectable

While oral NAD⁺ precursors (NR, NMN) can raise tissue levels over a period of weeks, temporal alignment matters. By the time oral supplementation meaningfully elevates pools, those windows have closed.

Injectable NAD⁺ (IV or IM) produces a rapid, high-amplitude peak. Circulating levels rise within the infusion window and remain elevated for hours. This peak can be synchronized with exercise, ensuring that when oxidative demand spikes, the cofactor supply is present.

Fat as Fuel

Fat burning is not one step. It is a chain, and every link must be present:

1. Retatrutide → releases fat from storage (mobilization)
2. L-Carnitine → transports fat into mitochondria (logistics)
3. MOTS-c → programs mitochondria to prefer fat (the switch)
4. NAD⁺ → provides capacity to complete combustion (execution)

Retatrutide Mobilizes Fat

The glucagon arm signals adipose tissue to release fatty acids into circulation and primes the liver for oxidation. Fat leaves storage and enters the bloodstream. This is step one—but fat circulating in blood is not fat being burned.

L-Carnitine Transports Fat

Long-chain fatty acids cannot cross the inner mitochondrial membrane on their own. They require the carnitine shuttle—a transport system that carries fat into the mitochondrial matrix where oxidation can occur.

Without adequate carnitine, fatty acids accumulate outside the furnace, unavailable for burning. L-Carnitine ensures the logistics work: fat gets from bloodstream to mitochondria.

But here is the critical point most approaches miss: fat sitting inside mitochondria is not the same as fat being oxidized.

Mitochondria can burn either glucose or fat. In metabolically inflexible individuals—which describes most of the modern population—the system is biased toward glucose. Fat may be present, transported, available, but the machinery isn't set up to prefer it. The mitochondria are waiting for glucose—and fat remains unable to be converted into energy.

MOTS-c Triggers Fat as Fuel

It is a sixteen-amino-acid peptide encoded in mitochondrial DNA, released during exercise as a retrograde signal from mitochondria to the nucleus. MOTS-c activates AMPK, the energy sensor that detects when fuel is being actively burned. AMPK then triggers downstream pathways—FOXO transcription factors, PGC-1α—that shift cellular preference toward fat oxidation. The mitochondria stop waiting for glucose and start burning what's available.

This is not stimulation. It is reprogramming. MOTS-c tells the system to behave as if it just finished an endurance session—preferentially oxidizing fat, sparing glycogen, building metabolic flexibility. It creates the preference for fat that transport alone cannot provide.

NAD⁺ Combusts

Once mitochondria are programmed to prefer fat, they need the cofactor capacity to actually complete β-oxidation. This is where the architecture comes full circle: NAD⁺, introduced as the capacity layer, becomes essential for every cycle of fatty acid breakdown. The electron transport chain uses NAD⁺ as its primary carrier. Sirtuins, which coordinate the stress responses that make this whole system adaptive, require NAD⁺ to function.

Without adequate NAD⁺ pools—and they are typically depleted with age, chronic inflammation, and metabolic dysfunction—the chain stalls at the final step.

Fat is mobilized, transported, and the mitochondria are programmed to burn it, but they cannot complete the process. This manifests as the worst of both worlds: the deficit exists, the machinery is running, but energy never arrives. The subjective experience is fatigue, brain fog, and the familiar sense of being "wired but underpowered"—precisely the complaint of many GLP-1 users whose oxidative capacity was never addressed.

The Full Chain

Skip any link and the chain weakens. Endogenous carnitine exists, but in metabolically compromised individuals—depleted stores, high oxidative demand—supplemental L-Carnitine ensures transport isn't the bottleneck. L-Carnitine without MOTS-c delivers fat to mitochondria that don't want it. MOTS-c without NAD⁺ programs oxidation that cannot complete. Each layer assumes the others are supporting.

This is why isolated interventions fail. Taking L-Carnitine alone doesn't produce dramatic fat loss—transport without programming or capacity accomplishes little. MOTS-c alone is limited by depleted NAD⁺ pools. The architecture works because it addresses the full chain, not a single step.

Tesamorelin: The Anabolic Layer

The first four layers—retatrutide, NAD⁺, L-Carnitine, MOTS-c—create a deficit and route it toward fat. But they do not actively protect lean tissue. Under strong catabolic pressure, muscle can still be sacrificed if nothing signals its preservation.

Tesamorelin adds the anabolic counterweight. It is a GHRH analog that restores pulsatile, endogenous growth hormone secretion rather than supplying exogenous GH directly. The distinction matters: tesamorelin preserves the body's natural rhythm—GH pulses clustered at night, modulated by sleep and nutrition—rather than flattening it with constant external supply.

Clinical Trials

In clinical trials, tesamorelin produces selective effects. Visceral adipose tissue decreases while subcutaneous fat is relatively spared. Hepatic fat fraction drops. Lean mass is preserved or modestly increased. These are not generic weight-loss outcomes; they are recomposition outcomes—changes in where fat sits and what tissue is protected.

The visceral fat reduction creates a feedback loop. Visceral fat is metabolically active in the wrong direction: it secretes inflammatory cytokines, worsens insulin resistance, and impairs the very fuel-routing the stack is trying to achieve. As visceral fat decreases, insulin sensitivity improves, and the fat-as-fuel bias becomes easier to maintain. Tesamorelin doesn't just protect muscle—it clears an obstacle that was making oxidation harder.

Circadian Timing

Circadian alignment matters here. GH secretion is naturally nocturnal. Tesamorelin amplifies this pattern, supporting a clean division: daytime for AMPK-dominant oxidation and training, nighttime for mTOR-dominant repair and lean-mass preservation. The anabolic layer doesn't fight the oxidative layers; it occupies a different temporal window.

Who Benefits

Tesamorelin is not a first-line agent for everyone. It is highest utility for cases where visceral adiposity is elevated (e.g. in metabolically compormised South Asians), where lean-mass preservation under strong catabolic pressure is a prioirty, or where the individual is already training-engaged and running the lower layers.

IGF-1 monitoring is required. Active malignancy is a contraindication. This is a high-threshold layer with real benefits and real oversight requirements.

The Protocol

The dual-axis approach is not a menu. It is a progression, where each layer assumes the previous ones are in place.

Note that the layer order (how you build the stack) differs from the chain order (how fat gets burned). NAD⁺ is layer one because capacity must be present before anything else makes sense—but metabolically, NAD⁺ executes at the final step, completing the combustion that the earlier chain links made possible. The architecture is organized by dependency, not by metabolic sequence.

Layer	Agent	Role
Foundation	Retatrutide	Central metabolic stabilization; preserves oxidation
1	NAD⁺	Cofactor capacity for oxidation
2	L-Carnitine	Fatty acid transport into mitochondria
3	MOTS-c	Mitochondrial programming; AMPK bias
4	Tesamorelin	GH axis; lean mass protection; visceral fat targeting

Most benefit for relatively healthy, training-engaged adults comes from the first four layers. Tesamorelin is added when visceral adiposity or lean-mass preservation demands it.

The outcomes are different from GLP-1 monotherapy:

• Body composition shifts, not just weight loss. Fat decreases; muscle is preserved or gained. The scale may move less dramatically, but the mirror and the DEXA tell a different story.

• Energy increases rather than decreases. The oxidative machinery is running, not stalled. Fat becomes available fuel rather than inert storage.

• Visceral and hepatic fat are targeted specifically. The metabolically dangerous depots shrink, improving insulin sensitivity and reducing inflammatory load.

• Training capacity is preserved. The deficit doesn't collapse performance because the system has the capacity to burn what it's mobilizing.

This is recomposition, not weight loss. The distinction matters. Weight loss asks only that the scale move. Recomposition asks that fat leave while muscle stays—a harder problem that requires more than appetite suppression.

Who This Is For

This architecture is not for everyone.

For severe obesity—BMI above 40, significant comorbidities, urgent need for large-scale weight reduction—GLP-1 monotherapy may be appropriate. The trade-offs (lean mass loss, potential fatigue) may be acceptable when the alternative is continued metabolic catastrophe. The dual-axis approach is more complex and more expensive; it is not always the right tool.

The dual-axis architecture is for:

• Training-engaged adults who want recomposition, not just weight loss. People who care about muscle, performance, and body composition, not just the number on the scale.

• Those already on GLP-1 therapy experiencing the downsides—fatigue despite weight loss, difficulty training, feeling metabolically flat. The peripheral scaffold addresses what appetite suppression cannot.

• People who tried GLP-1s and quit because the side effects weren't worth it. The architecture offers a different approach: lower central doses, preserved oxidation, supported capacity.

• Anyone dissatisfied with "cut then bulk" cycles that produce temporary results and long-term frustration. Dual-axis recomposition is designed to be sustainable—metabolic coherence rather than metabolic warfare.

The approach requires more: more compounds, more monitoring, more understanding of what each layer does. It is not simpler than taking semaglutide alone. But for those whose goals extend beyond weight loss to actual metabolic health, the complexity is the point. The body is a system. Treating one axis while ignoring the other produces one-axis results.

Dual-axis recomposition treats both. The deficit is created and directed. Fat is mobilized, transported, and burned. Muscle is protected. Energy increases. The outcome is not just lighter—it is leaner, stronger, and metabolically coherent.