PwPepwise

SHLP-2

Energy & Cells

a.k.a. Small Humanin-Like Peptide 2

Mitochondrial-derived peptide

SHLP-2 (Small Humanin-Like Peptide 2) is a naturally occurring peptide encoded within the mitochondrial genome.

§Dosing at a glance

1 protocol · from the research
What it's forDoseHow oftenHowFor how long
Animal (mouse) — metabolic / obesity model2.5 mg/kgTwice dailyIntraperitonealInjected into the abdominal cavity (research use).3 days

Approximate values pulled from the research — double-check before dosing.

§01Summary

SHLP-2 (Small Humanin-Like Peptide 2) is a naturally occurring peptide encoded within the mitochondrial genome, belonging to a family of mitochondria-derived peptides (MDPs) that act as hormones to coordinate the body's energy and metabolic responses. Unlike most hormones encoded in the cell nucleus, SHLP-2 originates from the mitochondria — the cellular powerhouses — and appears to function as a systemic signal linking mitochondrial health to whole-body metabolism.

In early animal research, SHLP-2 may protect against diet-induced obesity and may improve insulin sensitivity, working in part by activating appetite-suppressing neurons in the brain1. Studies in obese mice suggest it may also promote calorie-burning thermogenesis and favorably shift metabolic markers in the blood, including those related to antioxidant defense and inflammation2. A receptor for SHLP-2 — known as CXCR7 — has been identified, providing a molecular handle for understanding how the peptide communicates its effects throughout the body1. Separately, circulating levels of SHLP-2 have been explored as a potential biomarker in certain disease contexts3. Human evidence is actively developing, and the peptide represents an emerging area of research in metabolic health and healthy aging.

This is the layperson summary. Mechanism, dosing, the evidence base, and the published literature are in the sections below — every claim links to its source.

§02In depth

SHLP-2 is a 12-amino acid peptide encoded within the 16S ribosomal RNA region of the human mitochondrial genome, placing it within the family of mitochondrial-derived peptides (MDPs) that includes humanin and MOTS-c. These peptides are translated from short open reading frames within mitochondrial RNA and are secreted into circulation, functioning as retrograde mitochondrial signals that coordinate nuclear and systemic responses to cellular stress and energetic demand.

A major mechanistic advance was the identification of CXCR7 (C-X-C Chemokine Receptor 7, also designated ACKR3) as the functional receptor mediating SHLP-2's metabolic effects1. CXCR7 is an atypical chemokine receptor with known roles in immune cell trafficking, cardiovascular development, and neuronal signaling. Upon SHLP-2 binding, downstream signaling in hypothalamic neurons — specifically pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus — appears to be engaged, leading to suppression of food intake and activation of thermogenic programs1. This central mechanism was demonstrated through both systemic and intracerebroventricular administration, suggesting that SHLP-2 may access or functionally engage the central nervous system through either direct CNS penetration or peripheral-to-central relay mechanisms1.

At the systemic metabolic level, SHLP-2 treatment in diet-induced obese mice modulated plasma metabolite profiles in a pattern consistent with insulin sensitization2. Particularly notable were robust changes in glutathione metabolism, implicating an antioxidant mechanism of action in which SHLP-2 may reduce oxidative stress burden associated with metabolic dysfunction2. Concurrent modulation of sphingolipid metabolic pathways is mechanistically significant, as ceramide and sphingosine-1-phosphate species are established mediators of insulin resistance, inflammation, and cardiovascular risk — suggesting a possible unified mechanism linking SHLP-2's metabolic and potentially cardioprotective effects2.

Pharmacokineticdata for SHLP-2 in humans have not been published. In animal models, the peptide was administered intraperitoneally at 2.5 mg/kg twice daily2 and also via intracerebroventricular routes1, but formal characterization of half-life, bioavailability, volume of distribution, and metabolic clearance in any species remains an active area of investigation. As an endogenously circulating peptide, SHLP-2 levels are measurable in plasma and appear to vary with physiological and pathological states, supporting its potential utility both as a therapeutic agent and as a circulating biomarker3.

§04Evidence & efficacy

Evidence base
29Studies
7Human
2Animal

SHLP-2 has demonstrated metabolic activity in preclinical models, with preliminary evidence suggesting it may reduce diet-induced obesity and may improve insulin sensitivity in mice1,2.

In a 2023 study, systemic and intracerebroventricular administration of SHLP-2 may suppress food intake and promote thermogenesis through activation of pro-opiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus, producing protection against high-fat diet-induced obesity and improved insulin sensitivity in male mice1. A complementary metabolomics study found that SHLP-2 treatment may modulate plasma amino acid and lipid metabolite profiles in diet-induced obese mice in a manner consistent with improved insulin sensitivity and reduced metabolic dysfunction2. Notably, glutathione pathway modulation observed in treated animals suggests a potential antioxidant dimension to SHLP-2's metabolic effects2, while changes in sphingolipid metabolism may link its metabolic and cardiovascular-relevant activities through a shared pathway2.

Low circulating levels of SHLP-2 have also been explored as a potential biomarker for disease risk3, suggesting that endogenous SHLP-2 signaling plays a physiologically meaningful role. Human efficacy data is actively emerging across multiple research fronts.

§05Safety

Published safety data for SHLP-2 is limited to the preclinical setting, and no formal human safety or tolerability studies have been reported to date.

In the animal studies conducted, no explicit adverse events or tolerability concerns were reported. The IP administration of 2.5 mg/kg twice daily for 3 days in diet-induced obese mice produced no noted adverse findings2. Similarly, both systemic and intracerebroventricular administration in the hypothalamic neuron study did not report observable adverse events in male mice1.

From a mechanistic standpoint, SHLP-2's identified receptor, CXCR7 (also known as ACKR3), is expressed in immune and cardiovascular tissues beyond its metabolic roles1. This biological relationship is an area that ongoing research will help characterize. The modulation of sphingolipid and glutathione metabolic pathways observed in treated animals represents biologically active systemic effects whose full safety implications in humans are being investigated2.

The existing preclinical studies were conducted exclusively in male mice1, and sex-specific safety considerations in female subjects remain an active area of investigation.

§06History

SHLP-2 was first characterized as part of a broader discovery effort by Pinchas Cohen and colleagues at the USC Leonard Davis School of Gerontology, who identified a family of small open reading frames embedded within the 16S ribosomal RNA region of the human mitochondrial genome. This work, building on the earlier discovery of humanin in the early 2000s, revealed that the mitochondrial genome encodes a previously unappreciated set of bioactive peptides — collectively termed mitochondrial-derived peptides (MDPs). The SHLPs (Small Humanin-Like Peptides 1–6) were characterized structurally and shown to share partial sequence homology with humanin while exhibiting distinct biological potencies.

Early research established that circulating SHLP-2 levels may serve as a biomarker, with low levels reported in association with prostate cancer risk3, positioning the peptide at the intersection of aging biology and oncology. The metabolic properties of SHLP-2 were characterized in a 2019 metabolomics study demonstrating insulin-sensitizing and antioxidant-associated metabolite shifts in diet-induced obese mice2. A significant mechanistic milestone arrived in 2023 with the identification of CXCR7 as the functional receptor for SHLP-2 and the demonstration of hypothalamic POMC neuron activation as a central mechanism of its anti-obesity effects in male mice1. These findings established SHLP-2 as one of the most mechanistically well-characterized MDPs in the metabolic arena, and it currently represents an active and growing area of preclinical and translational research in obesity, insulin resistance, and aging-related metabolic disease.

§07References